Chronic Diseases and Translational Medicine

Volume 10, Issue 4 pp. 263-280

REVIEW

Open Access

S-acylation of Ca²⁺ transport proteins in cancer

Sana Kouba,

Sana Kouba

orcid.org/0000-0003-4221-2952

Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland

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Nicolas Demaurex,

Corresponding Author

Nicolas Demaurex

[email protected]

Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland

Correspondence Nicolas Demaurex, Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.

Email: [email protected]

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Sana Kouba,

Sana Kouba

orcid.org/0000-0003-4221-2952

Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland

Search for more papers by this author

Nicolas Demaurex,

Corresponding Author

Nicolas Demaurex

[email protected]

Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland

Correspondence Nicolas Demaurex, Department of Cell Physiology and Metabolism, Centre Médical Universitaire, University of Geneva, Geneva, Switzerland.

Email: [email protected]

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First published: 14 August 2024

https://doi.org/10.1002/cdt3.146

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Abstract

Alterations in cellular calcium (Ca²⁺) signals have been causally associated with the development and progression of human cancers. Cellular Ca²⁺ signals are generated by channels, pumps, and exchangers that move Ca²⁺ ions across membranes and are decoded by effector proteins in the cytosol or in organelles. S-acylation, the reversible addition of 16-carbon fatty acids to proteins, modulates the activity of Ca²⁺ transporters by altering their affinity for lipids, and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers. Here, we compile studies reporting an association between Ca²⁺ transporters or S-acylation enzymes with specific cancers, as well as studies reporting or predicting the S-acylation of Ca²⁺ transporters. We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca²⁺ transport proteins involved in cancer.

Key points

S-acylation is a reversible lipid post-translational modification that adds a long-chain fatty acid to specific cysteine residues of target proteins.
S-acylation is mediated by membrane zDHHC enzymes, also known as protein acyl transferases, and is reversed by de-acylases or acyl protein thioesterases.
Enzymes that mediate the addition and removal of lipids via S-acylation are implicated in cancer.
Calcium transporters are signaling proteins implicated in cancer growth and progression.
Calcium transporters are targets for S-acylation, and their lipid modification is relevant for cancer research.

1 INTRODUCTION

Protein S-acylation, also referred to as S-palmitoylation, is a critical post-translational modification that involves the reversible attachment of a long-chain fatty acid, typically 16-carbon palmitate acid, to specific cysteine residues of target proteins via a thioester bond.¹ S-acylation enhances protein hydrophobicity, promoting their interaction with non-polar structures like lipid bilayers, thereby influencing protein subcellular localization, trafficking, and interactions with other molecules.² This process is catalyzed by palmitoyl-transferases proteins encoded by 23 genes in humans. Despite sharing a conserved Zinc finger Asp-HiS-HiS-Cys (zDHHC) motif, these proteins exhibit diverse cellular distributions and unique substrate preferences and efficiencies during the acylation process. The removal of fatty acid groups is mediated by Acyl Protein Thioesterases (APT1&2) and α/β-hydrolase Domain-Containing Proteins (ABHD).³ The dynamic and reversible process of S-acylation enables precise regulation of protein function in both space and time.

Cancer cells exhibit hallmark traits such as sustained proliferation, resistance to apoptosis, and increased metastatic potential due to abnormalities in intracellular signaling, metabolic pathways, and gene regulation networks.⁴ Several signaling proteins implicated in cancer are targets for S-acylation⁵ including Ras proteins,⁶ Src family kinases,⁷ Wnt signaling components,⁸ Protein kinases C (PKC),⁹ and calcium (Ca²⁺) transporters.¹⁰ Abnormal Ca²⁺ signals contribute to carcinogenesis¹¹ and post-translational modifications of Ca²⁺ transporters have been linked to cancer,¹² but the contribution of S-acylation in this process remains unexplored.

In this review, we summarize recent work reporting the involvement of acylation enzymes in cancer, as well as studies documenting or predicting the S-acylation of Ca²⁺ transporters. We then examine the potential impact of S-acylation on the pathophysiology of a subset of Ca²⁺ transport proteins implicated in cancer.

2 S-ACYLATION: KEY ENZYMES AND BIOCHEMICAL MECHANISMS

The human genome encodes 23 zDHHC enzymes bearing four or six transmembrane (TM) domains, with the DHHC cysteine-rich domain situated between TM 2 and 3. The catalytic reaction of zDHHC enzymes occurs through two sequential steps.¹³ First, the DHHC cysteine within the active site undergoes auto-acylation by interacting with an acyl-coenzyme A (acyl-CoA) donor. Second, this acyl chain is transferred from the DHHC cysteine to cysteine residues of target proteins (Figure 1A). The majority of TM zDHHCs are situated in the endoplasmic reticulum (ER), while others are found in the Golgi, the nuclear envelope¹⁴ or dispersed throughout the early secretory pathway (ER-Golgi intermediate compartment ERGIC pathway).¹⁵ Some zDHHCs exhibit dual localization¹⁶ at the plasma membrane (PM) and in the endocytic network.

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

S-acylation cycle and enzymes. (A) A target protein is S-acylated at the thiol group of particular cysteine residue by zDHHC enzymes, using acyl-CoA as acyl donor. zDHHC proteins are initially auto-S-fatty acylated on the DHHC cysteine residue, releasing free CoA, followed by the transfer of the acyl group to the acceptor cysteine residue of a substrate protein. (B) The thioester-tethered lipidation is eliminated through hydrolysis mediated by deacylases such as APTs. APTs are themselves S-acylated and contain a hydrophobic pocket to accept acylated substrates, positioning the lipidated cysteine of the substrate near the serine (Ser) residue of the active site. This process allows the regeneration of free thiol groups. zDHHC, Zinc finger Asp-HiS-HiS-Cys. The figure was created with www.biorender.com.

De-acylation enzymes employ a conserved catalytic serine to trigger a nucleophilic attack on the thioester carbonyl group,¹⁷ producing an intermediate ester subsequently hydrolyzed by water. De-acylation enzymes comprise acyl-protein thioesterases (APT1 and APT2, encoded by the LYPLA1 and LYPLA2 genes¹⁸), palmitoyl-protein thioesterase 1 and 2 (PPT1 and PPT2),¹⁹ and ABHD.^{20, 21} De-acylation begins with acyl-thioesterases binding to cell membranes (Figure 1B), via electrostatic interactions and the insertion of a hydrophobic loop into the membrane.¹⁷ S-acylation anchors thioesterases to the membrane, enabling the enzymes to detach the acyl chain from the membrane. They then position it within a hydrophobic pocket to ensure proper engagement of the thioester bond at the active site. Thioesterases exhibit diverse cellular distribution, with PPT1 and PPT2 localized inside late endosomes and/or lysosomes,³ APT2 and some ABHDs in the Golgi and PM, and others trafficked to different cellular compartments.¹⁷ How thioesterases navigate throughout the endomembrane systems to interact with their substrates is unclear, but their labile interactions with membranes enable a dynamic regulation of protein S-acylation.²²

3 TECHNICAL ASSAYS TO STUDY PROTEIN S-ACYLATION: BENEFITS AND LIMITATIONS

3.1 Metabolic labeling with radiolabelled palmitate

Radiolabelling techniques were developed in the 1980²³ with the aim of tagging cellular fatty acid pools using tritiated palmitate ([3H]-palmitate), followed by purification, electrophoresis, and autoradiography.²⁴ Despite their effectiveness in revealing rapid S-acylation dynamics, the use of [3H]-palmitate has declined due to challenges associated with significant sample amounts and long exposure times for autoradiographs. It is also limited in providing insights into S-acylation stoichiometry. There are also other limitations for radiolabelling, such as the preference of some zDHHC-PATs for fatty acid chain lengths other than 16 carbons and the potential metabolism of labeled palmitate, leading to its incorporation into different cellular fatty acid pools.

3.2 Acyl-biotin exchange and acyl-resin assisted capture

The acyl-biotin exchange (ABE) assay²⁵ enables affinity purification and proteome-level characterization of S-acylated proteins by converting the acyl modification into a stable biotin adduct (Figure 2). This process relies on the high reactivity of the thioester bond and its removal by weak bases such as hydroxylamine (NH₂OH). Another assay, known as acyl-resin-assisted capture (Acyl-RAC), improved the process by combining steps of thioester cleavage and capture by thiol-reactive sepharose beads (Figure 2).²⁶ Both Acyl-RAC and ABE allow direct assessment of S-acylation levels at steady state but they cannot capture S-acylation/de-acylation dynamics or changes in S-acylation states. They also require multiple washing steps after cysteine alkylation and/or biotinylation. To ensure complete alkylation of free cysteines and specificity in thioester cleavage, strategies such as initial reducing steps are employed to help reduce false positives.

3.3 Cysteine site-specific PEGylation

This technique is an adaptation of the ABE/Acyl-RAC assays (Figure 2). After thioester cleavage, the resulting free thiol is capped with PEG-N-ethylmaleimide to introduce a mass shift compared to the non-acylated protein. This causes a “laddering” effect in the protein of interest on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blot.²⁷ The degree of laddering reveals the number of S-acylation sites and the stoichiometry of S-acylation. Available cysteine-reactive PEG maleimides, induce a 5 kDa or 10 kDa shift. However, this technique is limited to proteins migrating as single bands smaller than 100 kDa on SDS-PAGE. Nevertheless, PEGylation remains the only reliable method for quantifying S-acylation sites and detecting transitions between different S-acylation states.

3.4 Click chemistry

Click chemistry is based on metabolic labeling of a clickable analog of palmitic acid, typically 17-octadecyonic acid (17-ODYA). This step is followed by copper-catalyzed alkyne-azide cycloaddition reaction (Cu(I)-catalyzed [3 + 2] Huisgen) known as “Clicking” and incubation with an appropriate azide or alkyne-containing click chemistry probe²⁸ (Figure 2). These probes have been helpful in identifying new acylated proteins, validation of modification sites, and understanding of fatty acid selectivity, including the characterization and manipulation of carbon lengths and zDHHC-PAT preferences. This technique is limited by low stoichiometry protein detection but reduces false positives compared to ABE/AcylRAC.

4 BIOINFORMATIC TOOLS TO STUDY PROTEIN S-ACYLATION

4.1 SwissPalm

SwissPalm serves as a centralized cross-species database, compiling reported S-acylation substrates from curated proteome datasets and experimental validations in the literature.²⁹ SwissPalm offers a search functionality that allows users to look up any given protein and see how frequently it has been identified in acyl-proteome datasets or validated experimentally. Swisspalm provides S-acylation site prediction through tools like PalmPred³⁰ and CSS-Palm³¹ which facilitates comparison of protein lists with its database, supporting various filtering options. When associated to other bioinformatics tools (such as Gene Ontology), it helps in understanding how S-acylation might influence biological pathways. However, the database has limitations, including a substantial statistical false discovery rate associated with mass spectrometry and background detection issues from hydroxylamine-dependent protein capture. Experimental validation and determination of biological relevance have so far been limited to a small number of proteins, and proteomics studies do not directly confirm the S-acylation of all identified hits.

4.2 BrainPalmSeq

BrainPalmSeq is an online database of RNA-seq data focusing on S-acylation regulation in the brain. It compiles gene expression information from various RNA-seq studies, offering standardized interactive heatmaps.³² Users can explore expression of genes that regulate S-acylation in the brain, including zDHHC enzymes, deacylation enzymes, and known zDHHC accessory proteins. Across various brain regions or cell types. The limitations include potential biases in the reanalyzed data, the dependency on the quality of the original RNA-seq studies, and the complexity of accurately predicting functional outcomes based exclusively on expression patterns.

4.3 CellPalmSeq

CellPalmSeq is similar to BrainPalmSeq, and focuses on human single-cell and whole RNA-seq data from numerous cancer and non-human cell lines.³³ For cancer research, it helps identify S-acylation and deacylation enzymes enriched in cancer cell lines, potentially informing targeted cancer therapies. It also offers interactive heatmaps to compare gene expression patterns related to S-acylation regulation across datasets. Bar charts allow comparisons for gene expression across various tissues, cell types, or cancer cell lines. Limitations may include biases in the datasets analyzed, variability in RNA-seq data quality across different studies, and challenges in directly translating gene expression into functional implications without additional experimental validation.

5 S-ACYLATION AND DE-ACYLATION ENZYMES INVOLVED IN CANCER

In this section, we review recent studies linking zDHHC and APT enzymes to cancer as candidate oncoproteins, tumor suppressors, or prognostic markers.

5.1 zDHHC1

zDHHC1 was identified as potential tumor suppressor frequently silenced by epigenetic modifications like promoter methylation in cancer tissues and cell lines.³³ In MCF7 breast and HONE1 nasopharyngeal carcinoma cell lines, restoring zDHHC1 expression by methylation inhibition or by ectopic expression promoted apoptosis and cell cycle arrest, reversed epithelial to mesenchymal transition (EMT) and stemness biomarkers, and decreased tumor growth and metastasis in xenografts. zDHHC1 downregulation decreased ER stress and pyroptosis markers GRP78, CHOP, NLRP3, and IL-1β, indicating that zDHHC1 promotes proinflammatory cell death. Subsequently, zDHHC1 was identified as a tumor suppressor in cohorts of prostate cancer (PCa) patients.³⁴ Among six pyroptosis-related genes, zDHHC1 was negatively associated with a higher probability of biochemical recurrence, immune infiltration, and degraded clinicopathological features. zDHHC1 downregulation promoted the proliferation and migration of DU-145 and PC-3 cells and their growth and metastasis in xenografts, while its overexpression promoted pyroptosis, confirming the implication of this isoform in proinflammatory-driven cell death.

5.2 zDHHC2

Loss of zDHHC2 heterozygosity was associated with early metastatic recurrence after liver transplantation in a cohort of 40 patients with hepatocellular carcinoma (HCC).³⁵ zDHHC2 expression was decreased in HCC samples and cell lines while zDHHC2 overexpression inhibited proliferation, migration, and invasion in HCC cell lines, suggesting that zDHHC2 acts as tumor suppressor.³⁵ Accordingly, zDHHC2 expression was reduced in gastric tumor tissues from patients with gastric adenocarcinoma and was associated with lymph node metastasis and unfavorable prognosis.³⁶ In contrast, zDHHC2 was upregulated in renal cancer tissues and cell lines resistant to tyrosine kinase inhibitors (TKIs).³⁷ TKIs suppress the vascular endothelial growth factor (VEGF) signaling pathway, angiogenesis, and the progression of malignant tumors. Sunitinib, a TKI, has been approved as a first-line targeted agent for clear cell renal cell carcinoma (ccRCC),³⁸ and resistance to sunitinib has been documented in this context.³⁹ Amongst the pathways involved in resistance to TKIs is lipid metabolism.⁴⁰ In cellular and mouse models of ccRCC, zDHHC2-mediated S-acylation contributed to sunitinib resistance by promoting the PM localization of acylglycerol kinase (AGK) and the subsequent activation of the AKT-mTOR pathway.³⁷

5.3 zDHHC3

The integrin α6β4, implicated in tumor progression,⁴¹ metastasis,⁴² and angiogenesis,⁴³ was reported to be S-acylated by the enzyme zDHHC3 in breast and PCa cell lines.⁴⁴ zDHHC3 downregulation decreased integrin signaling without affecting other integrins and reduced β4 phosphorylation and cell surface expression by promoting its endosomal degradation. zDHHC3 was linked to the programmed death-ligand 1 (PD-L1) axis in colon cancer cell lines.⁴⁵ PD-L1 blockade has revolutionized anticancer immunotherapy⁴⁶ and post-translational modifications control PD-L1 turnover, affecting the clinical response to anti-PD-1/PD-L1 therapies. zDHHC3 reportedly S-acylates PD-L1 at Cys272, preventing its lysosomal degradation. Inhibition of PD-L1 S-acylation by 2-bromo-palmitate or zDHHC3 silencing activated antitumor immunity in vitro and in mice models. A competitive inhibitor of PD-L1 S-acylation reduced PD-L1 expression in tumor cells, enhancing T-cell immunity. Reduced zDHHC3 expression correlated with unfavorable outcomes and high expression with better prognosis in kidney clear cell carcinoma (KIRC),⁴⁷ a disease with poor prognosis and limited therapeutic options.⁴⁸ Genes linked to high zDHHC3 expression in KIRC were mainly involved in ion transport and included the sodium-hydrogen exchanger SLC9A2. In Caki-2 cells zDHHC3 ablation decreased SLC9A2 S-acylation and prevented apoptosis. zDHHC3 is linked to reduced patient survival in breast cancer (BrCa) and upregulated in metastatic tumors.⁴⁹ zDHHC3 downregulation decreased the size of primary tumor and metastasis in MDA-MB-231 xenografts and promoted oxidative stress, focal adhesion kinase (FAK) and STAT3 activation⁵⁰ and the secretion of senescence-associated proteins.⁵¹ Additionally, zDHHC3-suppressed tumors exhibited increased recruitment of innate immune cells associated with senescent tumor clearance.⁵²

5.4 zDHHC4

zDHHC4 upregulation correlates with tumor grade and poor prognosis in glioblastoma (GBM)⁵³ and was linked to glycogen synthase kinase 3β (GSK3β), an enzyme involved in malignant progression.^{54, 55} zDHHC4-mediated S-acylation of GSK3β at Cys14 enhanced resistance to temozolomide, enriching GBM stem cell populations and increasing their self-renewal capacities by promoting STAT3 interactions with the histone methyltransferase EZH.⁵⁶

5.5 zDHHC5

zDHHC5 expression was also linked to stemness and malignant growth in glioma. In a cohort of sixty patients bearing p53 mutations associated with resistance to therapy, zDHHC5 expression correlated with p53 mutations.⁵⁷ Mutated p53 transcriptionally upregulated zDHHC5 along with the nuclear transcription factor NF-Y, enhancing the self-renewal capacity and tumorigenicity of glioma stem cells (GSCs). Downregulation of zDHHC5 decreased neurosphere formation and invasiveness. EZH2 was identified as a substrate for zDHHC5, with cysteines 571 and 576 being required for EZH2 S-acylation. Another study linked zDHHC5 to glioma via the S-acylation of FAK,⁵⁸ an enzyme that promotes cell migration and invasion.⁵⁹ zDHHC5 knockdown disrupted FAK S-acylation and membrane distribution, impairing proliferation and invasion of glioma cancer cells, while a catalytically inactive zDHHC5 Cys134S mutant reduced glioma xenografts growth. Elevated zDHHC5 protein expression also correlated with poor survival in non-small cell lung cancer (NSCLC).⁶⁰ Downregulation of zDHHC5 inhibited the growth of NSCLC lines without affecting normal human bronchial epithelial lines, reducing cell proliferation, colony formation, and invasion. These effects were reversed by re-expression of wild-type zDHHC5 but not of the catalytically inactive mutant and tumor xenograft formation was also decreased upon zDHHC5 downregulation.

5.6 zDHHC6

The ER-resident zDHHC6 was reported to S-acylate the oncoprotein NRAS. Artemisinin (ART), an antimalarial compound with potent anticancer properties, was shown to covalently bind and inhibit zDHHC6, suppressing NRAS S-acylation and reducing the proliferation of HeLa and MCF7 cells.⁶¹

5.7 zDHHC7

zDHHC7 expression is reduced in human PCa tissues and this decline correlates with negative clinical outcomes.⁶² In the androgen receptor positive PCa cell lines LNCaP and 22Rv1, zDHHC7 overexpression inhibited the transcription of genes involved in the cell cycle and steroid biosynthesis pathways. zDHHC7 depletion increased the oncogenic properties of PCa cells, an effect reversed by zDHHC7 re-expression. In contrast, zDHHC7 expression is associated with poor prognosis in liver cancer⁶³ in a pathological loop involving the transcription factor STAT3. In HepG2 cells, zDHHC7 S-acylates STAT3 at Cys108, increasing the expression of STAT3 target genes, including HIF1α that in turn promotes zDHHC7 expression in a positive feedback loop.⁶⁴ Pharmacological inhibition of zDHHC7 reduced STAT3 S-acylation, decreased HIF1α levels, and inhibited HCC cell proliferation in vivo.

5.8 zDHHC8

zDHHC8 was implicated in mesothelioma, a cancer with poor prognosis due to its intrinsic radioresistance.⁶⁵ zDHHC8 knockdown improved the benefits of X-irradiation in mesothelioma cell lines,⁶⁶ increasing apoptotic and micronucleic cells arrested in the G2/M checkpoint, and suppressed tumor growth, reduced cell proliferation, and promoted apoptosis in tumor-bearing mice exposed to X-irradiation. zDHHC8 knockdown thus enhances the efficacy of radiation therapy in malignant mesothelioma by inducing cell cycle arrest. In GBM, zDHHC8 was reported to regulate the cystine/glutamate antiporter SLC7A11 implicated in ferroptosis, an iron-dependent type of programmed cell death characterized by the accumulation of lipid peroxides.⁶⁷ S-acylation of SLC7A11 at Cys327 by zDHHC8 was shown to prevent SLC7A11 polyubiquitination and degradation,⁶⁸ and phosphorylation of zDHHC8 at Ser299 by AMPKα1 to enhance zDHHC8-SLC7A11 interactions, further promoting SLC7A11 S-acylation and stabilization. zDHHC8 knockdown increased ferroptosis in GBM cells, leading to impaired cell survival, rescued by ectopic SLC7A11 expression. In GBM patients, zDHHC8 expression correlated with SLC7A11/AMPKα1 expression in glioma samples and high co-expression levels were associated with poor prognosis.

5.9 zDHHC9

zDHHC9 expression is upregulated in colon cancer and correlates with bad prognosis.⁶⁹ In human DLD-1 and mouse MC38 colon cancer cell lines, zDHHC9 expression promoted IFN-γ-induced JAK/STAT1 activation and PD-L1 upregulation. zDHHC9 knockdown promoted colon cancer cell proliferation in vitro but decreased tumor growth in vivo, increasing immune cell infiltration and enhancing T cell-mediated cytotoxicity. zDHHC9 silencing with nanoparticles also induced a considerable regression of pancreatic tumors and extended the survival of mice with transplantable pancreatic tumors,⁷⁰ enhancing inflammation and infiltration of anti-tumor immune effector cells and boosting anti-PD-L1 immunotherapy.

5.10 zDHHC11

The zDHHC11 gene is atypical as it generates three distinct transcripts: a standard mRNA (pczDHHC11), a linear long non-coding RNA (lnczDHHC11), and a circular RNA (circzDHHC11), all sharing 18 miR-150 binding sites implicated in tumor suppression. The three zDHHC11 transcripts were proposed to act as microRNA sponge to promote the growth of Burkitt lymphoma (BL),⁷¹ a highly aggressive B-cell lymphoma, by releasing the transcription factor c-MYB from miR-150-mediated repression.^{72, 73} Knockdown of circzDHHC11 inhibited the growth of BL cell lines but ectopic expression of circzDHHC11 had no effect on cell growth and did not rescue the growth inhibition enforced by miR-150 overexpression. Moreover, knockdown of circzDHHC11 still inhibited growth of BL cells lacking the miR-150 binding site region, indicating that circzDHHC11 promotes the growth of BL independently of miR-150 sequestration, likely at the post-transcriptional level.

5.11 zDHHC12

zDHHC12 is upregulated in high-grade serous ovarian cancer (HGSOC) and zDHHC12 knockdown or pharmacological inhibition with 2-bromo-palmitate sensitized HGSOC cells to cisplatin treatment in ovarian xenografts and in ascites-derived organoid of platinum-resistant ovarian cancer.⁷⁴ zDHHC12 was shown to mediate the S-acylation of membrane claudin-3 (CLDN3), a tight junction protein that positively correlates with ovarian cancer progression.⁷⁵ S-acylation of CLDN3 by zDHHC12 on three juxta-membrane cysteine residues (Cys181, Cys182, and Cys184) promotes CLDN3 PM localization and protein stability. In an ovarian cancer cell line, CLDN3 or zDHHC12 silencing disrupted CLDN3 S-acylation and abolished tumorigenesis.⁷⁶

5.12 zDHHC13

A protective role for zDHHC13 in skin cancer was uncovered by a spontaneous mutation in the zDHHC13 gene (Zdhhc13luc), leading to a premature stop codon and the production of a truncated zDHHC13 protein with loss-of-function.⁷⁷ Homozygous mutant mice^{Zdhhc13luc/Zdhhc13luc} developed hypotrichosis and skin abnormalities, including hyperplasia, hyperkeratosis, and increased epidermal thickness. The animals also exhibited higher susceptibility to skin carcinogenesis compared to wild-type littermates, as evidenced by highly proliferative keratinocytes and accelerated transition through epidermal layers following exposure to tumor-promoting agents and acute UVB exposure. The skin phenotype correlated with constitutive NF-κB activation and enhanced neutrophil elastase secretion, factors associated with carcinogenesis.⁷⁸ zDHHC13 was further shown to S-Acylate the melanocortin-1 receptor (MC1R),⁷⁹ a melanoma gene predictor associated with red hair color and DNA damage repair.^{80, 81} zDHHC13 phosphorylation by AMPK at Ser208 enhanced MC1R S-acylation, inhibiting UVB-induced transformation of human melanocytes in vitro and delaying melanoma development in mice.

5.13 zDHHC14

zDHHC14 was identified as a tumor suppressor in PCa.⁸² A common small deletion of zDHHC14 was found in testicular germ cell tumors, predominantly in heterozygous form. zDHHC14 RNA and protein levels were reduced in primary tumors and in a panel of PCa cell lines (PC-3, DU-145, 22RV1, LNCaP, and VCaP). Overexpression of zDHHC14 decreased viability of 22RV1 cells and suppressed tumor growth in a xenograft model through induction of apoptosis.

5.14 zDHHC15

High zDHHC15 expression was reported in glioma-associated datasets, correlating with malignant phenotypes and poorer prognosis,⁸³ an association confirmed by immunohistochemistry of glioma samples from human patients. zDHHC15 knockdown suppressed the proliferation and migration of U87 and U251 glioma cells, reducing cyclins B1/D and MMP2/9 expression, while zDHHC15 overexpression had opposite effects that were linked to STAT3 signaling.

5.15 zDHHC16

High zDHHC16 expression was reported in NSCLC tissues and cell lines and associated with epigenetic m6A methylation, as silencing of methyltransferases Si-METTL3 or si-METTL14 decreased zDHHC16 gene expression.⁸⁴ zDHHC16 upregulation increased glucose consumption and lactate excretion in NSCLC cells, a Warburg effect that promoted cancer cell growth and migration, and reduced CREB ubiquitination, preventing ferroptosis. Conversely, zDHHC16 silencing enhanced CREB ubiquitination, identifying CREB as a zDHHC16 target in NSCLC.

5.16 zDHHC17

zDHHC17 expression increases progressively along with MAP2K4 expression in glioma samples progressing from grades I to IV and correlates with poor survival.⁸⁵ zDHHC17 knockdown inhibited cell proliferation by promoting cell cycle arrest while zDHHC17 overexpression rescued cell cycle progression. zDHHC17 was further reported to interact with MAP2K4 and p38/JNK, enhancing malignant progression, the zDHHC17-MAP2K4-JNK/p38 signaling axis contributing to GSC enrichment and increasing their self-renewal capacity.

5.17 zDHHC18

zDHHC18 was shown to S-Acylate malate dehydrogenase 2 (MDH2), an enzyme of the TCA cycle, whose S-acylation levels were enhanced in samples from patients with high-grade serous ovarian cancer.⁸⁶ Silencing zDHHC18 suppressed MDH2 S-acylation, reducing mitochondrial respiration and proliferation of ovarian cancer cell lines. Re-expression of wild-type MDH2, but not of its S-acylation-deficient Cys138S mutant, restored mitochondrial respiration and enhanced the growth and clonogenicity of ovarian cancer cells in vitro and in nude mice injected with MDH2-knockout A2780 cells.

5.18 zDHHC19

zDHHC19 upregulation correlates with poor prognosis in osteosarcoma (OS) datasets and OS cell lines.⁸⁷ zDHHC19 silencing inhibited proliferation, invasion, and migration of OS cells and suppressed OS growth and lung metastasis in xenografts. zDHHC19 is a target of the tumor suppressor miR-940 and zDHHC19 overexpression mitigated the suppression of proliferation, migration, and invasion induced by miR-940. The pro-oncogenic effects of zDHHC19 involved the Wnt/β-catenin pathway, suggesting that a miR-940/zDHHC19 axis regulates the Wnt/β-catenin pathway in OS.

5.19 zDHHC20

zDHHC20 was linked to metastatic growth of pancreatic ductal adenocarcinoma (PDAC).⁸⁸ In a short hairpin RNA screen, zdhhc20 silencing impaired the metastatic potential but not the proliferation of PDA530Met and FC1199 PDAC mouse cell lines while in a genetically engineered PDAC mouse model, zdhhc20 disruption delayed liver and lung metastases without impacting primary tumor growth. The tumorigenicity of zdhhc20-deficient cells increased in immunocompromised mice and in mice depleted of NK cells, linking their oncogenic potential to defective innate immunity, and cell surface proteins potentially engaging in interactions with NK cells were identified by zDHHC20 substrate profiling.

5.20 zDHHC21

zDHHC21 was identified in a post-translational protein modifications screen as a regulator of oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML), and its substrate identified as the mitochondrial enzyme adenylate kinase 2 (AK2).⁸⁹ Chemical inhibition or genetic suppression of zDHHC21 weakened the stemness potential and induced the myeloid differentiation of drug-resistant leukemia stem cells, which rely on OXPHOS for survival. zDHHC21 depletion or inhibition prevented AK2 localization to the mitochondria and decreased OXPHOS and ATP production, inhibiting the growth and viability of AML cells and stem cells without impacting normal hematopoietic cells. zDHHC21 inhibition reduced the growth of patient-derived AML blasts injected in mice and sensitized AML blasts to the cytotoxic effects of chemotherapy in xenograft model of relapsed/refractory leukemia, highlighting the potential of zDHHC21 as a potential therapeutic target in AML.

5.21 zDHHC22

zDHHC22 expression was found to be reduced in oestrogen receptor (ER) negative BrCa specimens and cell lines, an effect attributed to the epigenetic methylation of its promoter, and low zDHHC22 expression correlated with good prognosis in BrCa patients.⁹⁰ Ectopic expression of WT, but not of S-acylation-deficient zDHHC22, reduced the proliferation of ER-negative BrCa cell lines, enhanced mTOR S-acylation, decreased AKT signaling, and restored MCF-7R cells sensitivity to oestrogen therapy.

5.22 LYPLA1

The de-acylation enzyme LYPLA1 (aka APT1) was reported to be highly expressed in the NSCLC cell line SPC-A-1 and in other lung cancer cell lines.⁹¹ LYPLA1 silencing inhibited the proliferation, migration, and invasion of the NSCLC cells and was associated with increased E-cadherin expression and decreased expression of the mesenchymal markers N-cadherin, vimentin, and SNAIL.

5.23 PPT1

The PPT1 was identified by photoaffinity pulldown as a target of a chloroquine derivative preventing lysosomes acidification and reducing melanoma cells viability and tumor growth in vivo,⁹² and was subsequently involved in HCC resistance to the kinase inhibitor sorafenib.⁹³ High PPT1 levels in HCC tissues correlated with poor prognosis and PPT1 was upregulated in sorafenib-resistant cell lines. In xenografts, PPT1 expression was associated with immune infiltration and the chloroquine derivative, presumably acting via PPT1, enhanced the anti-tumor immune response by promoting dendritic cell maturation and T cell activation. Ezurpimtrostat (aka GNS561), a small molecule accumulating in lysosomes, was also reported to inhibit PPT1 and its potential benefits for patients with advanced liver cancer are currently under evaluation.⁹⁴

5.24 PPT2

PPT2 expression was found to be reduced in ccRCC samples and low levels correlate with poor survival,⁹⁵ whereas in ccRCC cell lines PPT2 overexpression reduced EMT, cell migration, and invasion.

5.25 ABHD17

ABHD17 was found by dual pulse-chase metabolic labeling (17-ODYA) to be required for the de-palmitoylation of the oncoprotein N-Ras, while APT1 and APT2 were dispensable.²⁰ Overexpression of ABHD17A but not of catalytically dead (Ser211A) or N-truncated cytosolic mutants redistributed N-Ras away from the PM, as did mutation of N-Ras palmitoylated residue Cys181 or pharmacological inhibition of S-acylation. Knockdown of ABHD17 isoforms inhibited N-Ras palmitate turnover These data indicate that ABHD17 removes palmitate from N-Ras, altering its subcellular localization. ABHD17C was identified in the PDAC database as a potential biomarker for predicting prognosis and response to anti-PD1 therapy in pancreatic cancer patients.⁹⁶ ABHD17C overexpression increased glycolysis in pancreatic cancer cell lines and promoted their growth and resistance to anti-PD1 therapy when infected in mice, a phenotype associated with increased infiltration of myeloid-derived suppressor cells and reduced cytotoxic T cells infiltration, suggesting that ABHD17C promotes the formation of an acidic, immunosuppressive environment.

6 CA²⁺ TRANSPORT PROTEINS IN CANCER AND THEIR REGULATION BY S-ACYLATION

Since the discovery by Sydney Ringer of the role of calcium ions in cardiac contraction in 1883,⁹⁷ numerous studies have highlighted the crucial role of Ca²⁺ as intracellular second messengers. In response to homeostatic or environmental cues, the free intracellular Ca²⁺ concentration, maintained at nanomolar levels by pumps and exchangers, increases to micromolar levels due to the opening of Ca²⁺ channels in the PM and in the membrane of intracellular Ca²⁺ storing organelles.⁹⁸ The cytosolic Ca²⁺ elevations are encoded in time, space, amplitude, and frequency, and are decoded by specific effector proteins to enable the precise spatiotemporal control of cellular outcomes.⁹⁹

In the PM, three major classes of Ca²⁺-permeable channels have been identified, each with distinct characteristics (Figure 3). Voltage-gated Ca²⁺ channels (VGCCs) include CaV1 (L-type Ca²⁺ currents: α1S, α1C, α1D, and α1F), CaV2 (P/Q-type, N-type, and R-type Ca²⁺ currents: α1A, α1B, and α1E), and CaV3 (T-type Ca²⁺ currents: α1G, α1H, and α1I).¹⁰⁰ Transient receptor potential (TRP) channels comprise canonical (TRPC1-7), vanilloid (TRPV1-6), melastatin (TRPM1-8), ankyrin; TRPMA1-3), polycystin (TRPP1-3 and 5), and mucolipin (TRPML1-3) subfamilies, displaying a greater diversity in activation mechanisms and selectivity than any other group of ion channels.¹⁰¹ Ca²⁺ Release-Activated Ca²⁺ (CRAC) channels work through a mechanism known as store-operated Ca²⁺ entry (SOCE). Upon Ca²⁺ store depletion, ER-resident stromal interaction molecule (STIM [STIM1 and STIM2)) proteins are redistributed and interact with Orai (Orai1, Orai2 and Orai3) proteins on the PM, enabling Ca²⁺ influx.¹⁰²

In organelles, the opening of intracellular Ca²⁺ release channels such as inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) or ryanodine receptors (RYR) on the ER increase cytosolic Ca²⁺ levels (Figure 3). IP3 is generated by the engagement of G protein-coupled receptors (GPCRs) or receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), coupled to the phospholipase Cβ (PLCβ) and PLCγ isoforms.¹⁰³ In lysosomes and other acidic organelles, two-pore channels (TPCs) release Ca²⁺ in response to NAADP (nicotinic acid adenine dinucleotide phosphate). Restoration of basal Ca²⁺ levels is performed by Ca²⁺-ATPases, which pump cytosolic Ca²⁺ out of cells or back into storage organelles. Three Ca²⁺-ATPases have been identified, located in the membranes of the ER/SR (sarco-/endoplasmic reticulum Ca²⁺-ATPase [SERCA] pump), of the Golgi network (Secretary pathway Ca²⁺ ATPase [SPCA] pump), and in the PM (plasma membrane Ca²⁺ ATPase [PMCA] pump). In addition to the Ca²⁺-ATPases, Ca²⁺ extrusion through the PM can occur via the sodium/calcium exchanger NCX1.¹⁰⁴ Ca²⁺ buffering is also achieved by the mitochondrial Ca²⁺ uniporter (MCU) complex, which transports Ca²⁺ into mitochondria when cytoplasmic Ca²⁺ is rapidly elevated.¹⁰⁵

Ca²⁺ signals regulate cellular pathways involved in cancer onset or progression (Figure 4), including gene expression, cell proliferation, migration, and resistance to death signals.¹⁰⁶ In the tumor microenvironment, alterations in Ca²⁺ signaling are associated with malignant transformation, immune cell evasion¹⁰⁷ and resistance to cancer therapy.¹⁰⁸ Several classes of Ca²⁺ transporters, predominantly ion channels, are associated with the development and progression of human cancers and their implication is graphically illustrated along with relevant references in Figure 5. Table S2 summarizes the current knowledge on the S-acylation of Ca²⁺ transport proteins established by biochemical assays and predicted by the SwissPalm algorithm (criteria CSS-Palm 4.0: High confidence and PalmPred: High confidence score >0.4). Cross-referencing these datasets identifies NCX1, TRPC1, TRPC5, TRPM7, TRPM8, TRPML3, ORAI1/STIM1 and IP3R1 as cancer-associated Ca²⁺ transporters regulated by S-acylation via known enzyme(s). Studies exploring the potential role of the S-acylation of these Ca²⁺ transporters in cancer are discussed in the next chapter.

7 DOES S-ACYLATION OF CA²⁺ TRANSPORTERS CONTRIBUTE TO CANCER?

According to the studies summarized above, all the enzymes mediating the addition and removal of lipids by S-acylation are implicated in cancer (Table S1) and several PM and intracellular Ca²⁺ channels, pumps, and exchangers are associated with solid tumors (Figure 5). This is not unexpected given the multiplicity of cellular effector functions impacted by S-acylation and by Ca²⁺-dependent biochemical reactions. An increased expression of the genes coding for acyltransferases and thioesterases is a marker of bad prognostic, indicating that the turnover of these enzymes, rather than the lipidation state of their target proteins, limits cancer progression. On the other hand, an increased expression of the genes coding for Ca²⁺ transport proteins are usually associated with unfavorable outcomes, indicating that augmenting Ca²⁺ fluxes across cellular membranes promotes cancer progression. Notably, an increased S-acylation augments Ca²⁺ fluxes mediated by all the transporters that have been biochemically verified to be S-Acylated, except NCX1, whose function is decreased by S-acylation. Since NCX1 usually extrudes Ca²⁺ ions to restore basal cytosolic Ca²⁺ levels, the picture that emerges from the biochemical and functional studies is that the S-acylation of cellular Ca²⁺ transporters elevate the cytosolic Ca²⁺ concentration to levels that promote cancer progression. Of note, NCX1 was reported to operate in reverse mode in solid and hypoxic tumors,^147-149 and it will be interesting to establish the S-acylation status of NCX mediating Ca²⁺ uptake in this context.

S-acylation has two major impacts on the function of Ca²⁺ transport proteins. First, the enhanced affinity of acylated proteins for ordered lipids promotes their accumulation in membrane domains rich in cholesterol and sphingolipids, thereby altering the distribution of transporters in membranes and their interactions with regulatory proteins or lipids. Second, the addition of acyl chains can directly alter the conformation of TM domains, thereby affecting the gating, transport rates, and regulation of Ca²⁺ transporters. Both effects contribute to Ca²⁺ alterations in cancer models. Accumulation of SK3/Orai1 or TRPC1/SK3/Orai1 complexes in lipid rafts promotes Ca²⁺ entry and the migration or breast or colon cancer cells, while disruption of lipid rafts impairs Ca²⁺ entry and cell migration.^{150, 151} S-acylation promotes the accumulation of Orai1 in cholesterol-rich lipid domains¹⁵² and might contribute to malignancy by modulating its Ca²⁺ channel activity.¹⁵³ S-acylation also controls the affinity for lipids of the SOCE regulatory protein STIM1, which interacts with PM phospholipids via its exposed polybasic¹⁵⁴ and SOAR domains.¹⁵⁵ STIM1 is S-Acylated at Cys437 within SOAR, and this lipidation promotes STIM1 PM translocation and interactions with Orai1.¹⁵⁶ The coordinated S-acylation of Orai1 and STIM1 by zDHHC and APT enzymes might recruit both proteins to the same lipid domain to optimize Ca²⁺ fluxes, as suggested by studies linking enzymes involved in STIM-ORAI1 S-acylation/de-acylation and cancer (Table S1).

S-acylation enhances the activity and prevents the degradation of TRPM7¹⁵⁷ and TRPC5 channels.¹⁵⁸ These Ca²⁺ and Mg²⁺-permeable channels (for TRPM7) contribute to cancer chemoresistance¹¹² and promote cell proliferation, invasion and metastasis via their ion channel activity on the cell surface of cancer cells.^{126, 159} S-acylation also enhance the activity of IP3R1,¹⁶⁰ promoting cytosolic Ca²⁺ elevations via the release of Ca²⁺ from intracellular stores and the subsequent activation of SOCE. The Ca²⁺ released by IP3R1 is efficiently captured by mitochondria at membrane contact sites,¹⁶¹ and the dynamic S-acylation/de-acylation of IP3R1 promotes receptor tethering and signaling at these locations.¹⁶² IP3R1 S-acylation, therefore, enhances both the cytosolic and mitochondrial Ca²⁺ concentrations and might represent a particularly risky combination. Moreover, some zDHHC enzymes are positively regulated by Ca²⁺ elevations. zDHHC21 was recently shown to be a Ca²⁺/calmodulin-dependent enzyme critical for activation of naïve CD4⁺ T cells,¹⁶³ in a positive Ca²⁺ feedback loop mimicking constitutive channel activation. Finally, several pathways identified in Table S1 as mediating the oncogenic effects of zDHHC enzymes are directly or indirectly influenced by intracellular Ca²⁺ levels, including PI3K/Akt,¹⁶⁴ mTOR,^{165, 166} NF-κB,¹⁶⁷ and STAT3.^{168, 169} Further research should aim to clarify the mechanisms linking these enzymes and their targets to cancer progression.

8 CONCLUSION AND FUTURE PERSPECTIVES

Recent studies have linked cancer progression to alterations in S-acylation enzymes, which dynamically add lipids to proteins, and changes in proteins that regulate Ca²⁺ fluxes across cellular membranes. This review examines the link between cancer progression and these alterations in S-acylation enzymes and Ca²⁺ transporters, with a focus on the dynamic regulation of S-acylation of Ca²⁺ channels, pumps, and exchangers. These findings suggest that lipidated Ca²⁺ transporters could promote cancer, indicating a need for further research into this signaling axis to identify new therapeutic targets for cancer treatment. Currently, inhibitors lack specificity for zDHHC enzymes, highlighting the need for selective compounds. Examples include tetrazole-containing TTZ-1 and TTZ-2 compounds, which effectively inhibit zDHHC2-mediated S-acylation,¹⁷⁰ and acrylamide-based agents like cyanomyracrylamide, which blocks zDHHC20 activity.¹⁷¹ Additionally, targeting palmitate-derived palmitoyl-CoA with FASN (Fatty Acid Synthase) inhibitors such as TVB-3166 or TVB-3664 shows promise in inhibiting tumor growth, especially when combined with taxane-based treatments.¹⁷² Furthermore, inhibitors of de-acylation enzymes like ML-348 and ML-349 enhance tumor suppressor activities and induce apoptosis through mechanisms linked to ER stress and mTOR signaling¹⁷³ which are closely associated with Ca²⁺ signaling pathways. The development of precise inhibitors requires integrating structural biology with high-throughput screening techniques to identify compounds that can selectively target cancer cells through S-acylation without affecting normal cellular functions, ultimately opening new avenues for more effective and less toxic cancer therapies.

AUTHOR CONTRIBUTIONS

Sana Kouba: conceptualization, literature search, manuscript writing, and final editing. Nicolas Demaurex: supervision, manuscript writing, critical revision of the manuscript, and approval of the final version.

ACKNOWLEDGMENTS

The authors would like to express their appreciation to all those who contributed directly or indirectly to the research and compilation of this review article. This work is supported by Swiss National Science Foundation: 310030_189042.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

None.

Open Research

DATA AVAILABILITY STATEMENT

None.

Supporting Information

REFERENCES

1Main A, Fuller W. Protein S-palmitoylation: advances and challenges in studying a therapeutically important lipid modification. FEBS J. 2022; 289(4): 861-882. doi:10.1111/febs.15781
10.1111/febs.15781
CAS PubMed Web of Science® Google Scholar
2S Mesquita F, Abrami L, Linder ME, Bamji SX, Dickinson BC, Van Der Goot FG. Mechanisms and functions of protein s-acylation. Nat Rev Mol Cell Biol. 2024; 25: 488-509. doi:10.1038/s41580-024-00700-8
10.1038/s41580-024-00700-8
CAS PubMed Google Scholar
3Zeidman R, Jackson CS, Magee AI. Protein acyl thioesterases (Review). Mol Membr Biol. 2009; 26(1-2): 32-41. doi:10.1080/09687680802629329
10.1080/09687680802629329
CAS PubMed Google Scholar
4Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022; 12(1): 31-46. doi:10.1158/2159-8290.CD-21-1059
10.1158/2159-8290.CD-21-1059
CAS PubMed Web of Science® Google Scholar
5Li M, Zhang L, Chen CW. Diverse roles of protein palmitoylation in cancer progression, immunity, stemness, and beyond. Cells. 2023; 12(18):2209. doi:10.3390/cells12182209
10.3390/cells12182209
CAS PubMed Google Scholar
6Busquets-Hernández C, Triola G. Palmitoylation as a key regulator of ras localization and function. Front Mol Biosci. 2021; 8:659861. doi:10.3389/fmolb.2021.659861
10.3389/fmolb.2021.659861
CAS PubMed Web of Science® Google Scholar
7Sato I, Obata Y, Kasahara K, et al. Differential trafficking of Src, Lyn, Yes and Fyn is specified by the state of palmitoylation in the SH4 domain. J Cell Sci. 2009; 122(7): 965-975. doi:10.1242/jcs.034843
10.1242/jcs.034843
CAS PubMed Web of Science® Google Scholar
8Hosseini V, Dani C, Geranmayeh MH, Mohammadzadeh F, Ahmad SNS, Darabi M. Wnt lipidation: roles in trafficking, modulation, and function. J Cell Physiol. 2019; 234(6): 8040-8054. doi:10.1002/jcp.27570
10.1002/jcp.27570
CAS PubMed Web of Science® Google Scholar
9Liu Z, Xiao M, Mo Y, et al. Emerging roles of protein palmitoylation and its modifying enzymes in cancer cell signal transduction and cancer therapy. Int J Biol Sci. 2022; 18(8): 3447-3457. doi:10.7150/ijbs.72244
10.7150/ijbs.72244
CAS PubMed Web of Science® Google Scholar
10Néré R, Kouba S, Carreras-Sureda A, Demaurex N. S-acylation of Ca2+ transport proteins: molecular basis and functional consequences. Biochem Soc Trans. 2024; 52(1): 407-421. doi:10.1042/BST20230818
10.1042/BST20230818
CAS PubMed Google Scholar
11Bell DC, Leanza L, Gentile S, Sauter DR. News and views on ion channels in cancer: is cancer a channelopathy? Front Pharmacol. 2023; 14:1258933. doi:10.3389/fphar.2023.1258933
10.3389/fphar.2023.1258933
CAS Google Scholar
12Curran J, Mohler PJ. Alternative paradigms for ion channelopathies: disorders of ion channel membrane trafficking and posttranslational modification. Annu Rev Physiol. 2015; 77(1): 505-524. doi:10.1146/annurev-physiol-021014-071838
10.1146/annurev-physiol-021014-071838
CAS PubMed Google Scholar
13Mitchell DA, Vasudevan A, Linder ME, Deschenes RJ. Thematic review series: lipid posttranslational modifications. protein palmitoylation by a family of DHHC protein s-acyltransferases. J Lipid Res. 2006; 47(6): 1118-1127. doi:10.1194/jlr.R600007-JLR200
10.1194/jlr.R600007-JLR200
CAS PubMed Web of Science® Google Scholar
14Lemonidis K, Werno MW, Greaves J, et al. The zDHHC family of s-acyltransferases. Biochem Soc Trans. 2015; 43(2): 217-221. doi:10.1042/BST20140270
10.1042/BST20140270
CAS PubMed Web of Science® Google Scholar
15Ernst AM, Toomre D, Bogan JS. Acylation – a new means to control traffic through the Golgi. Front Cell Dev Biol. 2019; 7:109. doi:10.3389/fcell.2019.00109
10.3389/fcell.2019.00109
PubMed Web of Science® Google Scholar
16Greaves J, Carmichael JA, Chamberlain LH. The palmitoyl transferase DHHC2 targets a dynamic membrane cycling pathway: regulation by a C-terminal domain. Mol Biol Cell. 2011; 22(11): 1887-1895. doi:10.1091/mbc.e10-11-0924
10.1091/mbc.e10-11-0924
CAS PubMed Web of Science® Google Scholar
17Anwar MU, Van Der Goot FG. Refining s-acylation: structure, regulation, dynamics, and therapeutic implications. J Cell Biol. 2023; 222(11):e202307103. doi:10.1083/jcb.202307103
10.1083/jcb.202307103
CAS PubMed Google Scholar
18Davda D, Martin BR. Acyl protein thioesterase inhibitors as probes of dynamic S -palmitoylation. MedChemComm. 2014; 5(3): 268-276. doi:10.1039/C3MD00333G
10.1039/C3MD00333G
CAS PubMed Web of Science® Google Scholar
19Bellizzi JJ, Widom J, Kemp C, et al. The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. Proc Natl Acad Sci USA. 2000; 97(9): 4573-4578. doi:10.1073/pnas.080508097
10.1073/pnas.080508097
CAS PubMed Web of Science® Google Scholar
20Lin DTS, Conibear E. ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization. eLife. 2015; 4:e11306. doi:10.7554/eLife.11306
10.7554/eLife.11306
PubMed Web of Science® Google Scholar
21Yokoi N, Fukata Y, Sekiya A, Murakami T, Kobayashi K, Fukata M. Identification of PSD-95 depalmitoylating enzymes. J Neurosci. 2016; 36(24): 6431-6444. doi:10.1523/JNEUROSCI.0419-16.2016
10.1523/JNEUROSCI.0419-16.2016
CAS PubMed Web of Science® Google Scholar
22Kong E, Peng S, Chandra G, et al. Dynamic palmitoylation links cytosol-membrane shuttling of acyl-protein thioesterase-1 and acyl-protein thioesterase-2 with that of proto-oncogene H-Ras product and growth-associated protein-43. J Biol Chem. 2013; 288(13): 9112-9125. doi:10.1074/jbc.M112.421073
10.1074/jbc.M112.421073
CAS PubMed Web of Science® Google Scholar
23Schlesinger MJ, Magee AI, Schmidt MF. Fatty acid acylation of proteins in cultured cells. J Biol Chem. 1980; 255(21): 10021-10024. doi:10.1016/S0021-9258(19)70417-7
10.1016/S0021-9258(19)70417-7
CAS PubMed Google Scholar
24Jackson CS, Magee AI. Metabolic labeling with fatty acids. Curr Protoc Cell Biol. 2000; 5(1): 1-24. doi:10.1002/0471143030.cb0704s05
10.1002/0471143030.cb0704s05
Google Scholar
25Drisdel RC, Green WN. Labeling and quantifying sites of protein palmitoylation. Biotechniques. 2004; 36(2): 276-285. doi:10.2144/04362RR02
10.2144/04362RR02
CAS PubMed Web of Science® Google Scholar
26Forrester MT, Hess DT, Thompson JW, et al. Site-specific analysis of protein s-acylation by resin-assisted capture. J Lipid Res. 2011; 52(2): 393-398. doi:10.1194/jlr.D011106
10.1194/jlr.D011106
CAS PubMed Web of Science® Google Scholar
27Dozier J, Distefano M. Site-specific PEGylation of therapeutic proteins. Int J Mol Sci. 2015; 16(10): 25831-25864. doi:10.3390/ijms161025831
10.3390/ijms161025831
CAS PubMed Web of Science® Google Scholar
28Gao X, Hannoush RN. A decade of click chemistry in protein palmitoylation: impact on discovery and new biology. Cell Chem Biol. 2018; 25(3): 236-246. doi:10.1016/j.chembiol.2017.12.002
10.1016/j.chembiol.2017.12.002
CAS PubMed Google Scholar
29Blanc M, David F, Abrami L, et al. SwissPalm: protein palmitoylation database. F1000Research. 2015; 4: 261. doi:10.12688/f1000research.6464.1
10.12688/f1000research.6464.1
PubMed Google Scholar
30Kumari B, Kumar R, Kumar M. PalmPred: an SVM based palmitoylation prediction method using sequence profile information. PLoS One. 2014; 9(2):e89246. doi:10.1371/journal.pone.0089246
10.1371/journal.pone.0089246
PubMed Google Scholar
31Zhou F, Xue Y, Yao X, Xu Y. CSS-Palm: palmitoylation site prediction with a clustering and scoring strategy (CSS). Bioinformatics. 2006; 22(7): 894-896. doi:10.1093/bioinformatics/btl013
10.1093/bioinformatics/btl013
CAS PubMed Web of Science® Google Scholar
32Wild AR, Hogg PW, Flibotte S, et al. Exploring the expression patterns of palmitoylating and de-palmitoylating enzymes in the mouse brain using the curated RNA-seq database BrainPalmSeq. eLife. 2022; 11:e75804. doi:10.7554/eLife.75804
10.7554/eLife.75804
CAS PubMed Web of Science® Google Scholar
33Wild AR, Hogg PW, Flibotte S, et al. CellPalmSeq: a curated RNAseq database of palmitoylating and de-palmitoylating enzyme expression in human cell types and laboratory cell lines. Front Physiol. 2023; 14:1110550. doi:10.3389/fphys.2023.1110550
10.3389/fphys.2023.1110550
PubMed Web of Science® Google Scholar
34Luo CG, Gui CP, Huang GW, et al. Identification of ZDHHC1 as a pyroptosis inducer and potential target in the establishment of pyroptosis-related signature in localized prostate cancer. Oxid Med Cell Longevity. 2022; 2022: 1-25. doi:10.1155/2022/5925817
10.1155/2022/5925817
Web of Science® Google Scholar
35Peng C, Zhang Z, Wu J, et al. A critical role for ZDHHC2 in metastasis and recurrence in human hepatocellular carcinoma. BioMed Res Int. 2014; 2014: 1-9. doi:10.1155/2014/832712
Web of Science® Google Scholar
36Yan SM, Tang JJ, Huang CY, et al. Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma. PLoS One. 2013; 8(2):e56366. doi:10.1371/journal.pone.0056366
10.1371/journal.pone.0056366
CAS PubMed Google Scholar
37Sun Y, Zhu L, Liu P, Zhang H, Guo F, Jin X. ZDHHC2-mediated AGK palmitoylation activates AKT–mTOR signaling to reduce sunitinib sensitivity in renal cell carcinoma. Cancer Res. 2023; 83(12): 2034-2051. doi:10.1158/0008-5472.CAN-22-3105
10.1158/0008-5472.CAN-22-3105
CAS PubMed Google Scholar
38Atkins MB, Tannir NM. Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev. 2018; 70: 127-137. doi:10.1016/j.ctrv.2018.07.009
10.1016/j.ctrv.2018.07.009
CAS PubMed Web of Science® Google Scholar
39Li Q, Zhang Z, Fan Y, Zhang Q. Epigenetic alterations in renal cell cancer with TKIs resistance: from mechanisms to clinical applications. Front Genet. 2021; 11:562868. doi:10.3389/fgene.2020.562868.
10.3389/fgene.2020.562868
PubMed Google Scholar
40Germain N, Dhayer M, Boileau M, Fovez Q, Kluza J, Marchetti P. Lipid metabolism and resistance to anticancer treatment. Biology. 2020; 9(12):474. doi:10.3390/biology9120474
10.3390/biology9120474
CAS PubMed Google Scholar
41Stewart RL, O'Connor KL. Clinical significance of the integrin α6β4 in human malignancies. Lab Invest. 2015; 95(9): 976-986. doi:10.1038/labinvest.2015.82
10.1038/labinvest.2015.82
CAS PubMed Web of Science® Google Scholar
42Soung YH, Gil HJ, Clifford JL, Chung J. Role of α6β4 integrin in cell motility, invasion and metastasis of mammary tumors. Curr Protein Pept Sci. 2011; 12(1): 23-29. doi:10.2174/138920311795659399
10.2174/138920311795659399
CAS PubMed Google Scholar
43Desai D, Singh P, Van De Water L, LaFlamme SE. Dynamic regulation of integrin α ₆ β ₄ during angiogenesis: potential implications for pathogenic wound healing. Adv Wound Care. 2013; 2(8): 401-409. doi:10.1089/wound.2013.0455
10.1089/wound.2013.0455
Google Scholar
44Sharma C, Rabinovitz I, Hemler ME. Palmitoylation by DHHC3 is critical for the function, expression, and stability of integrin α6β4. Cell Mol Life Sci. 2012; 69(13): 2233-2244. doi:10.1007/s00018-012-0924-6
10.1007/s00018-012-0924-6
CAS PubMed Google Scholar
45Yao H, Lan J, Li C, et al. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng. 2019; 3(4): 306-317. doi:10.1038/s41551-019-0375-6
10.1038/s41551-019-0375-6
CAS PubMed Web of Science® Google Scholar
46Liu J, Chen Z, Li Y, Zhao W, Wu J, Zhang Z. PD-1/PD-L1 checkpoint inhibitors in tumor immunotherapy. Front Pharmacol. 2021; 12:731798. doi:10.3389/fphar.2021.731798
10.3389/fphar.2021.731798
CAS PubMed Web of Science® Google Scholar
47Zhang X, Hou J, Zhou G, Wang H, Wu Z. zDHHC3-mediated s-palmitoylation of SLC9A2 regulates apoptosis in kidney clear cell carcinoma. J Cancer Res Clin Oncol. 2024; 150(4): 194. doi:10.1007/s00432-024-05737-y
10.1007/s00432-024-05737-y
CAS PubMed Google Scholar
48Hu F, Zeng W, Liu X. A gene signature of survival prediction for kidney renal cell carcinoma by multi-omic data analysis. Int J Mol Sci. 2019; 20(22):5720. doi:10.3390/ijms20225720
10.3390/ijms20225720
CAS PubMed Web of Science® Google Scholar
49Sharma C, Wang HX, Li Q, et al. Protein acyltransferase DHHC3 regulates breast tumor growth, oxidative stress, and senescence. Cancer Res. 2017; 77(24): 6880-6890. doi:10.1158/0008-5472.CAN-17-1536
10.1158/0008-5472.CAN-17-1536
CAS PubMed Web of Science® Google Scholar
50Tanner JJ, Parsons ZD, Cummings AH, Zhou H, Gates KS. Redox regulation of protein tyrosine phosphatases: structural and chemical aspects. Antioxid Redox Signaling. 2011; 15(1): 77-97. doi:10.1089/ars.2010.3611
10.1089/ars.2010.3611
CAS PubMed Web of Science® Google Scholar
51Li Y, Deng W, Wu J, et al. TXNIP exacerbates the senescence and aging-related dysfunction of β cells by inducing cell cycle arrest through p38-p16/p21-CDK-Rb pathway. Antioxid Redox Signaling. 2023; 38(7-9): 480-495. doi:10.1089/ars.2021.0224
10.1089/ars.2021.0224
CAS PubMed Web of Science® Google Scholar
52Stokes KL, Cortez-Retamozo V, Acosta J, et al. Natural killer cells limit the clearance of senescent lung adenocarcinoma cells. Oncogenesis. 2019; 8(4): 24. doi:10.1038/s41389-019-0133-3
10.1038/s41389-019-0133-3
PubMed Google Scholar
53Zhao C, Yu H, Fan X, et al. GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2–STAT3 axis. Oncogenesis. 2022; 11(1): 28. doi:10.1038/s41389-022-00402-w
10.1038/s41389-022-00402-w
CAS PubMed Web of Science® Google Scholar
54Korur S, Huber RM, Sivasankaran B, et al. GSK3β regulates differentiation and growth arrest in glioblastoma. PLoS One. 2009; 4(10):e7443. doi:10.1371/journal.pone.0007443
10.1371/journal.pone.0007443
CAS PubMed Web of Science® Google Scholar
55Majewska E, Szeliga M. AKT/GSK3β signaling in glioblastoma. Neurochem Res. 2017; 42(3): 918-924. doi:10.1007/s11064-016-2044-4
10.1007/s11064-016-2044-4
CAS PubMed Web of Science® Google Scholar
56Kim E, Kim M, Woo DH, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell. 2013; 23(6): 839-852. doi:10.1016/j.ccr.2013.04.008
10.1016/j.ccr.2013.04.008
CAS PubMed Web of Science® Google Scholar
57Chen X, Ma H, Wang Z, Zhang S, Yang H, Fang Z. EZH2 palmitoylation mediated by ZDHHC5 in p53-mutant glioma drives malignant development and progression. Cancer Res. 2017; 77(18): 4998-5010. doi:10.1158/0008-5472.CAN-17-1139
10.1158/0008-5472.CAN-17-1139
CAS PubMed Web of Science® Google Scholar
58Wang Y, Shen N, Yang Y, et al. ZDHHC5-mediated s-palmitoylation of FAK promotes its membrane localization and epithelial-mesenchymal transition in glioma. Cell Commun Signaling. 2024; 22(1): 46. doi:10.1186/s12964-023-01366-z
10.1186/s12964-023-01366-z
CAS PubMed Google Scholar
59Chuang HH, Zhen YY, Tsai YC, et al. FAK in cancer: from mechanisms to therapeutic strategies. Int J Mol Sci. 2022; 23(3):1726. doi:10.3390/ijms23031726
10.3390/ijms23031726
CAS PubMed Web of Science® Google Scholar
60Tian H, Lu JY, Shao C, et al. Systematic siRNA screen unmasks NSCLC growth dependence by palmitoyltransferase DHHC5. Mol Cancer Res. 2015; 13(4): 784-794. doi:10.1158/1541-7786.MCR-14-0608
10.1158/1541-7786.MCR-14-0608
CAS PubMed Google Scholar
61Qiu N, Abegg D, Guidi M, Gilmore K, Seeberger PH, Adibekian A. Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6. Cell Chemical Biology. 2022; 29(3): 530-537.e7. doi:10.1016/j.chembiol.2021.07.012
10.1016/j.chembiol.2021.07.012
CAS PubMed Web of Science® Google Scholar
62Lin Z, Agarwal S, Tan S, et al. Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer. Oncogene. 2023; 42(26): 2126-2138. doi:10.1038/s41388-023-02718-2
10.1038/s41388-023-02718-2
CAS PubMed Google Scholar
63Lee C, Cheung ST. STAT3: an emerging therapeutic target for hepatocellular carcinoma. Cancers. 2019; 11(11):1646. doi:10.3390/cancers11111646
10.3390/cancers11111646
CAS PubMed Web of Science® Google Scholar
64Jiang Y, Xu Y, Zhu C, et al. STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice. Sci Signaling. 2023; 16(814):eadd2282. doi:10.1126/scisignal.add2282
10.1126/scisignal.add2282
CAS PubMed Google Scholar
65Hiriart E, Deepe R, Wessels A. Mesothelium and malignant mesothelioma. J Dev Biol. 2019; 7(2):7. doi:10.3390/jdb7020007
10.3390/jdb7020007
CAS PubMed Web of Science® Google Scholar
66Sudo H, Tsuji AB, Sugyo A, Ogawa Y, Sagara M, Saga T. ZDHHC8 knockdown enhances radiosensitivity and suppresses tumor growth in a mesothelioma mouse model. Cancer Sci. 2012; 103(2): 203-209. doi:10.1111/j.1349-7006.2011.02126.x
10.1111/j.1349-7006.2011.02126.x
CAS PubMed Web of Science® Google Scholar
67Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021; 12(8): 599-620. doi:10.1007/s13238-020-00789-5
10.1007/s13238-020-00789-5
CAS PubMed Web of Science® Google Scholar
68Wang Z, Wang Y, Shen N, et al. AMPKα1-mediated ZDHHC8 phosphorylation promotes the palmitoylation of SLC7A11 to facilitate ferroptosis resistance in glioblastoma. Cancer Lett. 2024; 584:216619. doi:10.1016/j.canlet.2024.216619
10.1016/j.canlet.2024.216619
CAS PubMed Google Scholar
69Chong X, Zhu L, Yu D, et al. ZDHHC9 promotes colon tumor growth by inhibiting effector T cells. Oncol Lett. 2022; 25(1): 5. doi:10.3892/ol.2022.13591
10.3892/ol.2022.13591
PubMed Google Scholar
70Lin Z, Huang K, Guo H, et al. Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment. Biomed Pharmacother. 2023; 161:114567. doi:10.1016/j.biopha.2023.114567
10.1016/j.biopha.2023.114567
CAS PubMed Google Scholar
71Liu Y, Zhao X, Seitz A, et al. Circular ZDHHC11 supports Burkitt lymphoma growth independent of its miR-150 binding capacity. Sci Rep. 2024; 14(1): 8730. doi:10.1038/s41598-024-59443-3
10.1038/s41598-024-59443-3
CAS PubMed Google Scholar
72Chen S, Wang Z, Dai X, et al. Re-expression of micro RNA -150 induces EBV -positive B urkitt lymphoma differentiation by modulating c-Myb in vitro. Cancer Sci. 2013; 104(7): 826-834. doi:10.1111/cas.12156
10.1111/cas.12156
CAS PubMed Web of Science® Google Scholar
73Dzikiewicz-Krawczyk A, Kok K, Slezak-Prochazka I, et al. ZDHHC11 and ZDHHC11B are critical novel components of the oncogenic MYC-miR-150-MYB network in Burkitt lymphoma. Leukemia. 2017; 31(6): 1470-1473. doi:10.1038/leu.2017.94
10.1038/leu.2017.94
CAS PubMed Web of Science® Google Scholar
74Zhang X, Liao X, Wang M, et al. Inhibition of palmitoyltransferase ZDHHC12 sensitizes ovarian cancer cells to cisplatin through ROS -mediated mechanisms. Cancer Sci. 2024; 115(4): 1170-1183. doi:10.1111/cas.16085
10.1111/cas.16085
CAS PubMed Google Scholar
75Tao D, Guan B, Li H, Zhou C. Expression patterns of claudins in cancer. Heliyon. 2023; 9(11):e21338. doi:10.1016/j.heliyon.2023.e21338
10.1016/j.heliyon.2023.e21338
CAS PubMed Google Scholar
76Yuan M, Chen X, Sun Y, et al. ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression. Acta Pharm Sin B. 2020; 10(8): 1426-1439. doi:10.1016/j.apsb.2020.03.008
10.1016/j.apsb.2020.03.008
CAS PubMed Web of Science® Google Scholar
77Perez CJ, Mecklenburg L, Jaubert J, et al. Increased susceptibility to skin carcinogenesis associated with a spontaneous mouse mutation in the palmitoyl transferase Zdhhc13 gene. J Invest Dermatol. 2015; 135(12): 3133-3143. doi:10.1038/jid.2015.314
10.1038/jid.2015.314
CAS PubMed Web of Science® Google Scholar
78Starcher B, O'Neal P, Granstein RD, Beissert S. Inhibition of neutrophil elastase suppresses the development of skin tumors in hairless mice. J Invest Dermatol. 1996; 107(2): 159-163. doi:10.1111/1523-1747.ep12329559
10.1111/1523-1747.ep12329559
CAS PubMed Web of Science® Google Scholar
79Sun Y, Li X, Yin C, et al. AMPK phosphorylates ZDHHC13 to increase MC1R activity and suppress melanomagenesis. Cancer Res. 2023; 83(7): 1062-1073. doi:10.1158/0008-5472.CAN-22-2595
10.1158/0008-5472.CAN-22-2595
CAS PubMed Google Scholar
80Quint K, Rhee J, Gruis N, et al. Melanocortin 1 receptor (MC1R) variants in high melanoma risk patients are associated with specific dermoscopic ABCD features. Acta Dermato Venereologica. 2012; 92(6): 587-592. doi:10.2340/00015555-1457
10.2340/00015555-1457
PubMed Web of Science® Google Scholar
81Chen S, Han C, Miao X, et al. Targeting MC1R depalmitoylation to prevent melanomagenesis in redheads. Nat Commun. 2019; 10(1): 877. doi:10.1038/s41467-019-08691-3
10.1038/s41467-019-08691-3
PubMed Web of Science® Google Scholar
82Yeste-Velasco M, Mao X, Grose R, et al. Identification of ZDHHC14 as a novel human tumour suppressor gene. J Pathol. 2014; 232(5): 566-577. doi:10.1002/path.4327
10.1002/path.4327
CAS PubMed Web of Science® Google Scholar
83Liu ZY, Lan T, Tang F, et al. ZDHHC15 promotes glioma malignancy and acts as a novel prognostic biomarker for patients with glioma. BMC Cancer. 2023; 23(1): 420. doi:10.1186/s12885-023-10883-6
10.1186/s12885-023-10883-6
PubMed Google Scholar
84Zeyu Liu L, Chuanqing Jing J, Wei Zhang Z. METTL3-mediated m6A modification enhances ZDHHC16 expression in nonsmall-cell lung cancer patients, attenuating ferroptosis by suppressing CREBubiquitination. Cell Mol Biol. 2024; 70(2): 30-37. doi:10.14715/cmb/2024.70.2.5
10.14715/cmb/2024.70.2.5
PubMed Google Scholar
85Chen X, Hao A, Li X, et al. Activation of JNK and p38 MAPK mediated by ZDHHC17 drives glioblastoma multiforme development and malignant progression. Theranostics. 2020; 10(3): 998-1015. doi:10.7150/thno.40076
10.7150/thno.40076
CAS PubMed Web of Science® Google Scholar
86Pei X, Li KY, Shen Y, et al. Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth. Sci China Life Sci. 2022; 65(10): 2017-2030. doi:10.1007/s11427-021-2048-2
10.1007/s11427-021-2048-2
CAS PubMed Web of Science® Google Scholar
87Liang S, Zhang X, Li J. Zinc finger Asp-His-His-Cys palmitoyl -acyltransferase 19 accelerates tumor progression through wnt/β-catenin pathway and is upregulated by miR-940 in osteosarcoma. Bioengineered. 2022; 13(3): 7367-7379. doi:10.1080/21655979.2022.2040827
10.1080/21655979.2022.2040827
CAS PubMed Web of Science® Google Scholar
88Tomić G, Sheridan C, Refermat AY, et al. Palmitoyl transferase ZDHHC20 promotes pancreatic cancer metastasis. Published online February 8, 2023. doi:10.1101/2023.02.08.527637
Google Scholar
89Shao X, Xu A, Du W, et al. Palmitoyltransferase ZDHHC21 regulates oxidative phosphorylation to induce differentiation block and stemness in AML. Blood Journal. 2023; 142(4):blood.2022019056. doi:10.1182/blood.2022019056
Google Scholar
90Huang J, Li J, Tang J, et al. ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance. Int J Biol Sci. 2022; 18(7): 2833-2850. doi:10.7150/ijbs.70544
10.7150/ijbs.70544
CAS PubMed Web of Science® Google Scholar
91Mohammed A, Zhang C, Zhang S, et al. Inhibition of cell proliferation and migration in non‑small cell lung cancer cells through the suppression of LYPLA1. Oncol Rep. 2018; 41(2): 973-980. doi:10.3892/or.2018.6857
PubMed Google Scholar
92Rebecca VW, Nicastri MC, Fennelly C, et al. PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discovery. 2019; 9(2): 220-229. doi:10.1158/2159-8290.CD-18-0706
10.1158/2159-8290.CD-18-0706
CAS PubMed Web of Science® Google Scholar
93Xu J, Su Z, Cheng X, et al. High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma. Cancer Cell Int. 2022; 22(1): 115. doi:10.1186/s12935-022-02508-y
10.1186/s12935-022-02508-y
CAS PubMed Google Scholar
94Harding JJ, Awada A, Roth G, et al. First-in-human effects of PPT1 inhibition using the oral treatment with GNS561/Ezurpimtrostat in patients with primary and secondary liver cancers. Liver Cancer. 2022; 11(3): 268-277. doi:10.1159/000522418
10.1159/000522418
CAS PubMed Web of Science® Google Scholar
95Yuan C, Xiong Z, Shi J, et al. Overexpression of PPT2 represses the clear cell renal cell carcinoma progression by reducing epithelial-to-mesenchymal transition. J Cancer. 2020; 11(5): 1151-1161. doi:10.7150/jca.36477
10.7150/jca.36477
CAS PubMed Google Scholar
96Zhang W, Xie Y, Yu X, et al. ABHD17C, a metabolic and immune-related gene signature, predicts prognosis and anti-PD1 therapy response in pancreatic cancer. Discov Oncol. 2023; 14(1): 87. doi:10.1007/s12672-023-00690-7.
10.1007/s12672-023-00690-7
CAS PubMed Google Scholar
97Ringer S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol. 1883; 4(1): 29-42. doi:10.1113/jphysiol.1883.sp000120
10.1113/jphysiol.1883.sp000120
CAS PubMed Google Scholar
98Bagur R, Hajnóczky G. Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Mol Cell. 2017; 66(6): 780-788. doi:10.1016/j.molcel.2017.05.028
10.1016/j.molcel.2017.05.028
CAS PubMed Web of Science® Google Scholar
99Parys JB, Guse AH. Full focus on calcium. Sci Signaling. 2019; 12(599):eaaz0961. doi:10.1126/scisignal.aaz0961
10.1126/scisignal.aaz0961
CAS PubMed Google Scholar
100Catterall WA. Voltage-Gated calcium channels. Cold Spring Harbor Perspect Biol. 2011; 3(8):a003947. doi:10.1101/cshperspect.a003947
10.1101/cshperspect.a003947
PubMed Web of Science® Google Scholar
101Vangeel L, Voets T. Transient receptor potential channels and calcium signaling. Cold Spring Harbor Perspect Biol. 2019; 11(6):a035048. doi:10.1101/cshperspect.a035048
10.1101/cshperspect.a035048
CAS PubMed Web of Science® Google Scholar
102 JA Kozak, JW Putney, eds., Calcium Entry Channels in Non-Excitable Cells. 1st ed. CRC Press; 2017. doi:10.1201/9781315152592
10.1201/9781315152592
Google Scholar
103Decuypere JP, Monaco G, Missiaen L, De Smedt H, Parys JB, Bultynck G. IP3 receptors, mitochondria, and Ca²⁺ signaling: implications for aging. J Aging Res. 2011; 2011: 1-20. doi:10.4061/2011/920178
10.4061/2011/920178
Google Scholar
104Brini M, Carafoli E. The plasma membrane Ca2+ ATPase and the plasma membrane sodium calcium exchanger cooperate in the regulation of cell calcium. Cold Spring Harbor Perspect Biol. 2011; 3(2):a004168. doi:10.1101/cshperspect.a004168
10.1101/cshperspect.a004168
PubMed Web of Science® Google Scholar
105Giorgi C, Marchi S, Pinton P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol. 2018; 19(11): 713-730. doi:10.1038/s41580-018-0052-8
10.1038/s41580-018-0052-8
CAS PubMed Web of Science® Google Scholar
106Roberts-Thomson SJ, Chalmers SB, Monteith GR. The calcium-signaling toolkit in cancer: remodeling and targeting. Cold Spring Harbor Perspect Biol. 2019; 11(8):a035204. doi:10.1101/cshperspect.a035204
10.1101/cshperspect.a035204
CAS PubMed Web of Science® Google Scholar
107Wu L, Lian W, Zhao L. Calcium signaling in cancer progression and therapy. FEBS J. 2021; 288(21): 6187-6205. doi:10.1111/febs.16133
10.1111/febs.16133
CAS PubMed Web of Science® Google Scholar
108Marchi S, Giorgi C, Galluzzi L, Pinton P. Ca²⁺ fluxes and cancer. Mol Cell. 2020; 78(6): 1055-1069. doi:10.1016/j.molcel.2020.04.017
10.1016/j.molcel.2020.04.017
CAS PubMed Web of Science® Google Scholar
109Pinto MCX, Kihara AH, Goulart VAM, et al. Calcium signaling and cell proliferation. Cellular Signalling. 2015; 27(11): 2139-2149. doi:10.1016/j.cellsig.2015.08.006
10.1016/j.cellsig.2015.08.006
CAS PubMed Web of Science® Google Scholar
110Patergnani S, Danese A, Bouhamida E, et al. Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer. Int J Mol Sci. 2020; 21(21):8323. doi:10.3390/ijms21218323
10.3390/ijms21218323
CAS PubMed Web of Science® Google Scholar
111Roderick HL, Cook SJ. Ca2+ signalling checkpoints in cancer: remodelling Ca2+ for cancer cell proliferation and survival. Nat Rev Cancer. 2008; 8(5): 361-375. doi:10.1038/nrc2374
10.1038/nrc2374
CAS PubMed Web of Science® Google Scholar
112Kouba S, Hague F, Ahidouch A, Ouadid-Ahidouch H. Crosstalk between Ca2+ signaling and cancer stemness: the link to cisplatin resistance. Int J Mol Sci. 2022; 23(18):10687. doi:10.3390/ijms231810687
10.3390/ijms231810687
CAS PubMed Google Scholar
113Sukumaran P, Nascimento Da Conceicao V, Sun Y, et al. Calcium signaling regulates autophagy and apoptosis. Cells. 2021; 10(8):2125. doi:10.3390/cells10082125
10.3390/cells10082125
CAS PubMed Web of Science® Google Scholar
114Alharbi A, Zhang Y, Parrington J. Deciphering the role of Ca2+ signalling in cancer metastasis: from the bench to the bedside. Cancers. 2021; 13(2):179. doi:10.3390/cancers13020179
10.3390/cancers13020179
CAS PubMed Google Scholar
115Hammad AS, Machaca K. Store operated calcium entry in cell migration and cancer metastasis. Cells. 2021; 10(5):1246. doi:10.3390/cells10051246
10.3390/cells10051246
CAS PubMed Google Scholar
116Nong S, Han X, Xiang Y, et al. Metabolic reprogramming in cancer: mechanisms and therapeutics. MedComm. 2023; 4(2):e218. doi:10.1002/mco2.218
10.1002/mco2.218
CAS PubMed Web of Science® Google Scholar
117Dejos C, Gkika D, Cantelmo AR. The two-way relationship between calcium and metabolism in cancer. Front Cell Dev Biol. 2020; 8:573747. doi:10.3389/fcell.2020.573747
10.3389/fcell.2020.573747
PubMed Web of Science® Google Scholar
118Moccia F, Negri S, Shekha M, Faris P, Guerra G. Endothelial Ca2+ signaling, angiogenesis and vasculogenesis: just what it takes to make a blood vessel. Int J Mol Sci. 2019; 20(16):3962. doi:10.3390/ijms20163962
10.3390/ijms20163962
CAS PubMed Web of Science® Google Scholar
119Kim SK, Cho SW. The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment. Front Pharmacol. 2022; 13:868695. doi:10.3389/fphar.2022.868695
10.3389/fphar.2022.868695
CAS PubMed Web of Science® Google Scholar
120Hempel N, Trebak M. Crosstalk between calcium and reactive oxygen species signaling in cancer. Cell Calcium. 2017; 63: 70-96. doi:10.1016/j.ceca.2017.01.007
10.1016/j.ceca.2017.01.007
CAS PubMed Web of Science® Google Scholar
121Girault A, Ahidouch A, Ouadid-Ahidouch H. Roles for Ca2+ and K+ channels in cancer cells exposed to the hypoxic tumour microenvironment. Biochim Biophys Acta Mol Cell Res. 2020; 1867(4):118644. doi:10.1016/j.bbamcr.2020.118644
10.1016/j.bbamcr.2020.118644
CAS PubMed Web of Science® Google Scholar
122Tajada S, Villalobos C. Calcium permeable channels in cancer hallmarks. Front Pharmacol. 2020; 11:968. doi:10.3389/fphar.2020.00968
10.3389/fphar.2020.00968
CAS PubMed Web of Science® Google Scholar
123Antal L, Martin-Caraballo M. T-type calcium channels in cancer. Cancers. 2019; 11(2):134. doi:10.3390/cancers11020134
10.3390/cancers11020134
CAS PubMed Google Scholar
124Phan NN, Wang CY, Chen CF, Sun Z, Lai MD, Lin YC. Voltage-gated calcium channels: novel targets for cancer therapy. Oncol Lett. 2017; 14(2): 2059-2074. doi:10.3892/ol.2017.6457
10.3892/ol.2017.6457
CAS PubMed Web of Science® Google Scholar
125Cui C, Zhang Y, Liu G, Zhang S, Zhang J, Wang X. Advances in the study of cancer metastasis and calcium signaling as potential therapeutic targets. Explor Target Antitumor Ther. 2021; 2: 266-291. doi:10.37349/etat.2021.00046
CAS PubMed Google Scholar
126Marini M, Titiz M, Souza Monteiro De Araújo D, Geppetti P, Nassini R, De Logu F. TRP channels in cancer: signaling mechanisms and translational approaches. Biomolecules. 2023; 13(10):1557. doi:10.3390/biom13101557
10.3390/biom13101557
CAS PubMed Google Scholar
127Bai S, Wei Y, Liu R, et al. The role of transient receptor potential channels in metastasis. Biomed Pharmacother. 2023; 158:114074. doi:10.1016/j.biopha.2022.114074
10.1016/j.biopha.2022.114074
CAS PubMed Google Scholar
128Vashisht A, Trebak M, Motiani RK. STIM and Orai proteins as novel targets for cancer therapy. A review in the theme: cell and molecular processes in cancer metastasis. Am J Physiol Cell Physiol. 2015; 309(7): C457-C469. doi:10.1152/ajpcell.00064.2015
10.1152/ajpcell.00064.2015
CAS PubMed Web of Science® Google Scholar
129Ren R, Li Y. STIM1 in tumor cell death: angel or devil? Cell Death Discov. 2023; 9(1): 408. doi:10.1038/s41420-023-01703-8
10.1038/s41420-023-01703-8
CAS PubMed Web of Science® Google Scholar
130Tiffner A, Hopl V, Derler I. CRAC and SK channels: their molecular mechanisms associated with cancer cell development. Cancers. 2022; 15(1):101. doi:10.3390/cancers15010101
10.3390/cancers15010101
PubMed Google Scholar
131Zhang Q, Wang C, He L. ORAI Ca2+ channels in cancers and therapeutic interventions. Biomolecules. 2024; 14(4):417. doi:10.3390/biom14040417
10.3390/biom14040417
CAS PubMed Google Scholar
132Chalmers SB, Monteith GR. ORAI channels and cancer. Cell Calcium. 2018; 74: 160-167. doi:10.1016/j.ceca.2018.07.011
10.1016/j.ceca.2018.07.011
CAS PubMed Web of Science® Google Scholar
133Padányi R, Pászty K, Hegedűs L, et al. Multifaceted plasma membrane Ca 2+ pumps: from structure to intracellular Ca 2+ handling and cancer. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2016; 1863(6): 1351-1363. doi:10.1016/j.bbamcr.2015.12.011
10.1016/j.bbamcr.2015.12.011
CAS PubMed Web of Science® Google Scholar
134Roberts-Thomson SJ. Plasma membrane calcium pumps and their emerging roles in cancer. World J Biol Chem. 2010; 1(8):248. doi:10.4331/wjbc.v1.i8.248
10.4331/wjbc.v1.i8.248
PubMed Google Scholar
135Chovancova B, Liskova V, Babula P, Krizanova O. Role of sodium/calcium exchangers in tumors. Biomolecules. 2020; 10(9):1257. doi:10.3390/biom10091257
10.3390/biom10091257
CAS PubMed Google Scholar
136Chemaly ER, Troncone L, Lebeche D. SERCA control of cell death and survival. Cell Calcium. 2018; 69: 46-61. doi:10.1016/j.ceca.2017.07.001
10.1016/j.ceca.2017.07.001
CAS PubMed Web of Science® Google Scholar
137Monteith GR, Davis FM, Roberts-Thomson SJ. Calcium channels and pumps in cancer: changes and consequences. J Biol Chem. 2012; 287(38): 31666-31673. doi:10.1074/jbc.R112.343061
10.1074/jbc.R112.343061
CAS PubMed Web of Science® Google Scholar
138Feng MY, Rao R. New insights into store-independent Ca2+ entry: secretory pathway calcium ATPase 2 in normal physiology and cancer. Int J Oral Sci. 2013; 5(2): 71-74. doi:10.1038/ijos.2013.23
10.1038/ijos.2013.23
CAS PubMed Google Scholar
139Delierneux C, Kouba S, Shanmughapriya S, Potier-Cartereau M, Trebak M, Hempel N. Mitochondrial calcium regulation of Redox signaling in cancer. Cells. 2020; 9(2):432. doi:10.3390/cells9020432
10.3390/cells9020432
CAS PubMed Web of Science® Google Scholar
140Katoshevski T, Ben-Kasus Nissim T, Sekler I. Recent studies on NCLX in health and diseases. Cell Calcium. 2021; 94:102345. doi:10.1016/j.ceca.2020.102345
10.1016/j.ceca.2020.102345
CAS PubMed Web of Science® Google Scholar
141Pathak T, Gueguinou M, Walter V, et al. Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis. eLife. 2020; 9:e59686. doi:10.7554/eLife.59686
10.7554/eLife.59686
CAS PubMed Web of Science® Google Scholar
142Foulon A, Rybarczyk P, Jonckheere N, et al. Inositol (1,4,5)-Trisphosphate receptors in invasive breast cancer: a new prognostic tool? Int J Mol Sci. 2022; 23(6):2962. doi:10.3390/ijms23062962
10.3390/ijms23062962
CAS PubMed Google Scholar
143Rezuchova I, Hudecova S, Soltysova A, et al. Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells. Cell Death Dis. 2019; 10(3): 186. doi:10.1038/s41419-019-1433-4
10.1038/s41419-019-1433-4
PubMed Web of Science® Google Scholar
144Rosa N, Sneyers F, Parys JB, Bultynck G. Type 3 IP3 receptors: the chameleon in cancer. Int Rev Cell Mol Biol. 351. Elsevier; 2020: 101-148 In: doi:10.1016/bs.ircmb.2020.02.003
10.1016/bs.ircmb.2020.02.003
CAS PubMed Google Scholar
145Xu N, Zhang D, Chen J, He G, Gao L. Low expression of ryanodine receptor 2 is associated with poor prognosis in thyroid carcinoma. Oncol Lett. 2019; 18: 3605-3612. doi:10.3892/ol.2019.10732.
CAS PubMed Web of Science® Google Scholar
146Chen T, Zhang X, Ding X, et al. Ryanodine receptor 2 promotes colorectal cancer metastasis by the ROS/BACH1 axis. Mol Oncol. 2023; 17(4): 695-709. doi:10.1002/1878-0261.13350
10.1002/1878-0261.13350
CAS PubMed Web of Science® Google Scholar
147Sennoune SR, Santos JM, Hussain F, Martínez-Zaguilán R. Sodium calcium exchanger operates in the reverse mode in metastatic human melanoma cells. Cell Mol Biol (Noisy-le-grand). 2015; 61(7): 40-49.
CAS PubMed Google Scholar
148Long Z, Chen B, Liu Q, et al. The reverse-mode NCX1 activity inhibitor KB-R7943 promotes prostate cancer cell death by activating the JNK pathway and blocking autophagic flux. Oncotarget. 2016; 7(27): 42059-42070. doi:10.18632/oncotarget.9806
10.18632/oncotarget.9806
PubMed Google Scholar
149Szadvari I, Hudecova S, Chovancova B, et al. Sodium/calcium exchanger is involved in apoptosis induced by H2S in tumor cells through decreased levels of intracellular pH. Nitric Oxide. 2019; 87: 1-9. doi:10.1016/j.niox.2019.02.011
10.1016/j.niox.2019.02.011
CAS PubMed Web of Science® Google Scholar
150Chantôme A, Potier-Cartereau M, Clarysse L, et al. Pivotal role of the lipid raft SK3–Orai1 complex in human cancer cell migration and bone metastases. Cancer Res. 2013; 73(15): 4852-4861. doi:10.1158/0008-5472.CAN-12-4572
10.1158/0008-5472.CAN-12-4572
CAS PubMed Google Scholar
151Guéguinou M, Harnois T, Crottes D, et al. SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline. Oncotarget. 2016; 7(24): 36168-36184. doi:10.18632/oncotarget.8786
10.18632/oncotarget.8786
PubMed Google Scholar
152Carreras-Sureda A, Abrami L, Ji-Hee K, et al. S-acylation by ZDHHC20 targets ORAI1 channels to lipid rafts for efficient Ca2+ signaling by Jurkat T cell receptors at the immune synapse. eLife. 2021; 10:e72051. doi:10.7554/eLife.72051
10.7554/eLife.72051
CAS PubMed Web of Science® Google Scholar
153Derler I, Jardin I, Stathopulos PB, et al. Cholesterol modulates Orai1 channel function. Sci Signaling. 2016; 9(412). doi:10.1126/scisignal.aad7808
10.1126/scisignal.aad7808
PubMed Google Scholar
154Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nature Cell Biol. 2009; 11(3): 337-343. doi:10.1038/ncb1842
10.1038/ncb1842
CAS PubMed Web of Science® Google Scholar
155Cohen HA, Zomot E, Nataniel T, Militsin R, Palty R. The SOAR of STIM1 interacts with plasma membrane lipids to form ER-PM contact sites. Cell Rep. 2023; 42(3):112238. doi:10.1016/j.celrep.2023.112238
10.1016/j.celrep.2023.112238
CAS PubMed Web of Science® Google Scholar
156Kodakandla G, West SJ, Wang Q, et al. Dynamic S-acylation of the ER-resident protein stromal interaction molecule 1 (STIM1) is required for store-operated Ca2+ entry. J Biol Chem. 2022; 298(9):102303. doi:10.1016/j.jbc.2022.102303
10.1016/j.jbc.2022.102303
CAS PubMed Web of Science® Google Scholar
157Gao X, Kuo CW, Main A, et al. Palmitoylation regulates cellular distribution of and transmembrane Ca flux through TrpM7. Cell Calcium. 2022; 106:102639. doi:10.1016/j.ceca.2022.102639
10.1016/j.ceca.2022.102639
CAS PubMed Google Scholar
158Hong C, Choi SH, Kwak M, et al. TRPC5 channel instability induced by depalmitoylation protects striatal neurons against oxidative stress in Huntington's disease. Biochim Biophys Acta Mol Cell Res. 2020; 1867(2):118620. doi:10.1016/j.bbamcr.2019.118620
10.1016/j.bbamcr.2019.118620
CAS PubMed Google Scholar
159Köles L, Ribiczey P, Szebeni A, Kádár K, Zelles T, Zsembery Á. The role of TRPM7 in oncogenesis. Int J Mol Sci. 2024; 25(2):719. doi:10.3390/ijms25020719
10.3390/ijms25020719
CAS PubMed Google Scholar
160Fredericks GJ, Hoffmann FW, Rose AH, et al. Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex. Proc Natl Acad Sci USA. 2014; 111(46): 16478-16483. doi:10.1073/pnas.1417176111
10.1073/pnas.1417176111
CAS PubMed Google Scholar
161Atakpa-Adaji P, Ivanova A. IP3R at ER-mitochondrial contact sites: beyond the IP3R-GRP75-VDAC1 Ca2+ funnel. Contact. 2023; 6:25152564231181020. doi:10.1177/25152564231181020
10.1177/25152564231181020
Google Scholar
162Petkovic M, O'Brien CE, Jan YN. Interorganelle communication, aging, and neurodegeneration. Genes Dev. 2021; 35(7-8): 449-469. doi:10.1101/gad.346759.120
10.1101/gad.346759.120
CAS PubMed Google Scholar
163Bieerkehazhi S, Fan Y, West SJ, et al. Ca2+-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells. J Cell Sci. 2022; 135(5):jcs258186. doi:10.1242/jcs.258186
10.1242/jcs.258186
CAS PubMed Google Scholar
164Divolis G, Mavroeidi P, Mavrofrydi O, Papazafiri P. Differential effects of calcium on PI3K-Akt and HIF-1α survival pathways. Cell Biol Toxicol. 2016; 32(5): 437-449. doi:10.1007/s10565-016-9345-x
10.1007/s10565-016-9345-x
CAS PubMed Google Scholar
165Li RJ, Xu J, Fu C, et al. Regulation of mTORC1 by lysosomal calcium and calmodulin. eLife. 2016; 5:e19360. doi:10.7554/eLife.19360
10.7554/eLife.19360
PubMed Web of Science® Google Scholar
166Amemiya Y, Maki M, Shibata H, Takahara T. New insights into the regulation of mTOR signaling via Ca2+-Binding proteins. Int J Mol Sci. 2023; 24(4):3923. doi:10.3390/ijms24043923
10.3390/ijms24043923
CAS PubMed Google Scholar
167Lilienbaum A, Israël A. From calcium to NF-κB signaling pathways in neurons. Mol Cell Biol. 2003; 23(8): 2680-2698. doi:10.1128/MCB.23.8.2680-2698.2003
10.1128/MCB.23.8.2680-2698.2003
CAS PubMed Web of Science® Google Scholar
168Lu Y, Gu Y, Ding X, Wang J, Chen J, Miao C. Intracellular Ca²⁺ homeostasis and JAK1/STAT3 pathway are involved in the protective effect of propofol on BV2 microglia against hypoxia-induced inflammation and apoptosis. PLoS One. 2017; 12(5):e0178098. doi:10.1371/journal.pone.0178098
10.1371/journal.pone.0178098
PubMed Web of Science® Google Scholar
169Shiratori-Hayashi M, Yamaguchi C, Eguchi K, et al. Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca2+ signals in mice. J Allergy Clin Immunol. 2021; 147(4): 1341-1353. doi:10.1016/j.jaci.2020.06.039
10.1016/j.jaci.2020.06.039
CAS PubMed Web of Science® Google Scholar
170Salaun C, Takizawa H, Galindo A, et al. Development of a novel high-throughput screen for the identification of new inhibitors of protein S-acylation. J Biol Chem. 2022; 298(10):102469. doi:10.1016/j.jbc.2022.102469
10.1016/j.jbc.2022.102469
CAS PubMed Google Scholar
171Azizi SA, Delalande C, Lan T, Qiu T, Dickinson BC. Charting the chemical space of acrylamide-based inhibitors of zDHHC20. ACS Med Chem Lett. 2022; 13(10): 1648-1654. doi:10.1021/acsmedchemlett.2c00336
10.1021/acsmedchemlett.2c00336
CAS PubMed Google Scholar
172Heuer TS, Ventura R, Mordec K, et al. FASN inhibition and taxane treatment combine to enhance anti-tumor efficacy in diverse xenograft tumor models through disruption of tubulin palmitoylation and microtubule organization and FASN inhibition-mediated effects on oncogenic signaling and gene expression. EBioMedicine. 2017; 16: 51-62. doi:10.1016/j.ebiom.2016.12.012
10.1016/j.ebiom.2016.12.012
PubMed Web of Science® Google Scholar
173Chen Y, Li Y, Wu L. Protein s-palmitoylation modification: implications in tumor and tumor immune microenvironment. Front Immunol. 2024; 15:1337478. doi:10.3389/fimmu.2024.1337478
10.3389/fimmu.2024.1337478
CAS PubMed Google Scholar

Volume10, Issue4

December 2024

Pages 263-280

This article also appears in:

S-acylation of Ca2+ transport proteins in cancer

Abstract

Key points

1 INTRODUCTION

2 S-ACYLATION: KEY ENZYMES AND BIOCHEMICAL MECHANISMS

3 TECHNICAL ASSAYS TO STUDY PROTEIN S-ACYLATION: BENEFITS AND LIMITATIONS

3.1 Metabolic labeling with radiolabelled palmitate

3.2 Acyl-biotin exchange and acyl-resin assisted capture

3.3 Cysteine site-specific PEGylation

3.4 Click chemistry

4 BIOINFORMATIC TOOLS TO STUDY PROTEIN S-ACYLATION

4.1 SwissPalm

4.2 BrainPalmSeq

4.3 CellPalmSeq

5 S-ACYLATION AND DE-ACYLATION ENZYMES INVOLVED IN CANCER

5.1 zDHHC1

5.2 zDHHC2

5.3 zDHHC3

5.4 zDHHC4

5.5 zDHHC5

5.6 zDHHC6

5.7 zDHHC7

5.8 zDHHC8

5.9 zDHHC9

5.10 zDHHC11

5.11 zDHHC12

5.12 zDHHC13

5.13 zDHHC14

5.14 zDHHC15

5.15 zDHHC16

5.16 zDHHC17

5.17 zDHHC18

5.18 zDHHC19

5.19 zDHHC20

5.20 zDHHC21

5.21 zDHHC22

5.22 LYPLA1

5.23 PPT1

5.24 PPT2

5.25 ABHD17

6 CA2+ TRANSPORT PROTEINS IN CANCER AND THEIR REGULATION BY S-ACYLATION

7 DOES S-ACYLATION OF CA2+ TRANSPORTERS CONTRIBUTE TO CANCER?

8 CONCLUSION AND FUTURE PERSPECTIVES

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

CONFLICT OF INTEREST STATEMENT

ETHICS STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Figures

References

Related

Information

S-acylation of Ca²⁺ transport proteins in cancer

6 CA²⁺ TRANSPORT PROTEINS IN CANCER AND THEIR REGULATION BY S-ACYLATION

7 DOES S-ACYLATION OF CA²⁺ TRANSPORTERS CONTRIBUTE TO CANCER?