Junction plakoglobin regulates and destabilizes HIF2α to inhibit tumorigenesis of renal cell carcinoma
Ke Chen
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorJin Zeng
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330000 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorYi Sun
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorWei Ouyang
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorGan Yu
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorHui Zhou
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorYangjun Zhang
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorWeimin Yao
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorWei Xiao
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorJunhui Hu
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095 USA
Search for more papers by this authorJinchun Xing
Department of Urology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361003 P. R. China
Search for more papers by this authorKefeng Xiao
Department of Urology, The People's Hospital of Shenzhen City, Shenzhen, Guangdong, 518020 P. R. China
Search for more papers by this authorLily Wu
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095 USA
Search for more papers by this authorZhiqiang Chen
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorZhangqun Ye
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorCorresponding Author
Hua Xu
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Correspondence
Hua Xu, Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P. R. China.
Email: [email protected]
Search for more papers by this authorKe Chen
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorJin Zeng
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330000 P. R. China
These authors contributed equally to this work.
Search for more papers by this authorYi Sun
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorWei Ouyang
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorGan Yu
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorHui Zhou
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorYangjun Zhang
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorWeimin Yao
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorWei Xiao
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorJunhui Hu
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095 USA
Search for more papers by this authorJinchun Xing
Department of Urology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361003 P. R. China
Search for more papers by this authorKefeng Xiao
Department of Urology, The People's Hospital of Shenzhen City, Shenzhen, Guangdong, 518020 P. R. China
Search for more papers by this authorLily Wu
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095 USA
Search for more papers by this authorZhiqiang Chen
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorZhangqun Ye
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Search for more papers by this authorCorresponding Author
Hua Xu
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030 P. R. China
Hubei Institute of Urology, Wuhan, Hubei, 430030 P. R. China
Correspondence
Hua Xu, Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P. R. China.
Email: [email protected]
Search for more papers by this authorAbstract
Background
Increased hypoxia-inducible factor 2α (HIF2α) activation is a common event in clear cell renal cell carcinoma (ccRCC) progression. However, the function and underlying mechanism of HIF2α in ccRCC remains uninvestigated. We conducted this study to access the potential link between junction plakoglobin (JUP) and HIF2α in ccRCC.
Methods
Affinity purification and mass spectrometry (AP-MS) screening, glutathione-s-transferase (GST) pull-down and co-immunoprecipitation (Co-IP) assays were performed to detect the interacting proteins of HIF2α. Quantitative PCR (qPCR) and Western blotting were used to detect the expression of JUP in human ccRCC samples. Luciferase reporter assays, chromatin immunoprecipitation (ChIP), cycloheximide chase assays, and ubiquitination assays were conducted to explore the regulation of JUP on the activity of HIF2α. Cell Counting Kit-8 (CCK-8) assays, colony formation assays, transwell assays, and xenograft tumor assays were performed to investigate the effect of JUP knockdown or overexpression on the tumorigenicity of renal cancer cells.
Results
We identified JUP as a novel HIF2α-binding partner and revealed an important role of JUP in recruiting von Hippel-Lindau (VHL) and histone deacetylases 1/2 (HDAC1/2) to HIF2α to regulate its stability and transactivation. JUP knockdown promoted and overexpression suppressed the tumorigenicity of renal cell carcinoma in vitro and in vivo. Importantly, the low expression of JUP was found in clinical ccRCC samples and correlated with enhanced hypoxia scores and poor treatment outcomes.
Conclusion
Taken together, these data support a role of JUP in modulating HIF2α signaling during ccRCC progression and identify JUP as a potential therapeutic target.
Supporting Information
| Filename | Description |
|---|---|
| cac212142-sup-0001-FigureS1.tif822.3 KB | Fig. S1 Immunofluorescence staining of JUP in 15 specimens of ccRCC and adjacent normal tissues in a tissue array. Normal renal tissues and ccRCC samples were subjected to immunofluorescence staining with a JUP antibody. Abbreviations: JUP, junction plakoglobin; ccRCC, clear cell renal cell carcinoma. |
| cac212142-sup-0002-FigureS2.tif28.9 KB | Fig. S2 JUP has no effect on the cell growth in renal cancer cells. The viability of ACHN and 786-O cells was assessed at each time point as the absorbance at 450 nm (OD450) using a CCK8 kit. Data were plotted as the mean ± SD of 3 independent experiments, and analyzed by two-way ANOVA. Abbreviations: JUP, junction plakoglobin. |
| cac212142-sup-0003-FigureS3.tif277.1 KB | Fig. S3 VHL is important for JUP-mediated reduction of HIF2α stability. A, The effect of JUP on the endogenous HIF2α levels in 786-O cells. 786-O cells were transfected with HA-JUP (0, 0.4, or 1μg) plasmids. Cell lysates were subjected to SDS-PAGE followed by immunoblotting with anti-HIF2α, anti-HA, and anti-GAPDH antibody. B, The inhibitory effect of JUP on HIF2α levels is restored by co-expression of pVHL wild-type but not by pVHL (Y98N) mutant. 786-O cells stably expressing pVHL-WT (left) or pVHL-Y98N mutant (right) were transfected with HA-JUP (0, 0.4, or 1 μg) plasmids. Cell lysates were subjected to SDS-PAGE followed by immunoblotting with anti-HIF2α, anti-HA, and anti-GAPDH antibody. C, The effect of JUP on exogenously expressed hydroxylation-defective mutant HIF2α (P405A/P531A) levels. HEK293T cells were co-transfected with Flag-HIF2α (P405A/P531A) and HA-JUP (0, 0.4, or 1 μg) plasmids. Cell lysates were subjected to SDS-PAGE followed by immunoblotting with anti-HIF2α, anti-HA, and anti-GAPDH antibody. D, The effect of JUP knockdown on the stability of HIF2α in 786-O cells. 786-O cells stably expressing sh-JUP-1# or sh-LacZ (control) was treated with 100 μM cycloheximide and harvested at the indicated time points to examine HIF2α levels by Western blotting. Abbreviations: JUP, junction plakoglobin; HIF2α, hypoxia-inducible factor 2α; CHX, cycloheximide. |
| cac212142-sup-0004-FigureS4.tif163.2 KB | Fig. S4 JUP has no effect on HIF2α/ARNT dimerization. A, Effects of JUP on HIF2α-HIF1β interaction. 786-O cells were co-transfected with Flag-ARNT (0.5 μg), Strep II-HIF2α (0.5 μg), and HA-JUP (0, 0.4, or 1 μg) plasmids. Cell lysates were precipitated with anti-Flag antibody and immunoblotted with anti-HIF2α antibody. B, JUP binds to ARNT independent of HIF2α. 786-O cells were co-transfected with HA-JUP (0.5 μg), Flag-ARNT (0.5 μg), and/or Strep II-HIF2α (0 or 1 μg). At 48 h after transfection, the whole-cell lysates were extracted and followed by Flag-immunoprecipitations and immunoblotting with HA and HIF2α antibody. Abbreviations: JUP, junction plakoglobin; HIF2α, hypoxia-inducible factor 2α; ARNT, Aryl hydrocarbon receptor nuclear translocator; |
| cac212142-sup-0005-FigureS5.tif56.7 KB | Fig. S5. The inhibition effect of JUP on the HIF2α-DM signaling is weaker than that on WT HIF2α signaling for the HRE luciferase reporter. Hypoxia response element (HRE) luciferase reporter assay in HEK293T cells expressing the empty vector control (psi-Flag), Flag-HIF2α, Flag-HIF2α-DM (P405A and P531A double mutant), and HA-JUP, as indicated. ** P < 0.01 (Student's t-test). The data are presented as mean ± SD of 3 experiments. Abbreviations: JUP, junction plakoglobin; HIF2α, hypoxia-inducible factor 2α; HRE: hypoxia response elements; DM: double mutant. |
| cac212142-sup-0006-TableS1.docx21.1 KB | Supplementary Table S1. The primers used in the study |
| cac212142-sup-0007-TableS2.docx16.5 KB | Supplementary Table S2: Relationship between JUP expression and clinicopathological features of ccRCC patients in a TCGA cohort |
| cac212142-sup-0008-TableS3.xlsx1.2 MB | Supplementary Table S3: FPKM values of genes identified from 786-O cells stably expressing sh-JUP-1# or sh-LacZ using RNA-sequencing |
| cac212142-sup-0009-TableS4.xlsx24.9 KB | Supplementary Table S4: Gene Ontology analysis of JUP down-regulated genes |
| cac212142-sup-0010-TableS5.xlsx119.2 KB | Supplementary Table S5: Functional annotation of JUP down-regulated genes |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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