Review
The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer
Kendra K. Nordgren,
Andrew J. Skildum,
Kendra K. Nordgren
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA
Search for more papers by this authorCorresponding Author
Andrew J. Skildum
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA
Correspondence to: Andrew Skildum, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA. Tel.: (218) 349 1539; fax: (218)726-7937; e-mail: [email protected]Search for more papers by this authorKendra K. Nordgren,
Andrew J. Skildum,
Kendra K. Nordgren
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA
Search for more papers by this authorCorresponding Author
Andrew J. Skildum
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA
Correspondence to: Andrew Skildum, University of Minnesota Medical School, 1035 University Drive, Duluth, MN, 55812, USA. Tel.: (218) 349 1539; fax: (218)726-7937; e-mail: [email protected]Search for more papers by this authorAbstract
Background
Epigenetic control of gene expression is mediated by cytosine methylation/demethylation and histone modifications including methylation, acetylation and glycosylation. The epigenetic programme is corrupted in cancer cells to maintain a pattern of gene expression that leads to their de-differentiated, rapidly proliferating phenotype. Enzymes responsible for modifying histones and cytosine are sensitive to the cellular metabolite pool and can be activated by an increase in their substrates or inhibited by an increase in their products or competitors for substrate binding.
Methods
This review is based on publications identified on PubMed using a literature search of cytosine methylation, histone methylation, acetylation and glycosylation.
Results
In cancer, changes in glycolytic enzymes lead to increased production of serine, increasing the pool of S-adenosylmethionine (the major methyl donor for methylation reactions) and UDP-N-acetylglucosamine (a substrate for O-linked glycosylation of histones and cytosine methyltransferases). Mutations in tricarboxylic acid cycle enzymes lead to accumulation of fumarate, succinate and hydroxyglutarate, all of which inhibit demethylation of cytosine and histones. In contrast, proline catabolism produces α-ketoglutarate and reactive oxygen, both of which promote the activity of enzymes that remove methyl groups from cytosine and histones, and the key enzyme in proline catabolism acts as a tumour suppressor.
Conclusions
Our emerging understanding of how the epigenetic profiles are metabolically reprogrammed in cancer cells will lead to novel diagnostic and therapeutic targets for treatment of patients.
References
- 1Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646–74.
- 2Duran RV, MacKenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S et al. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Oncogene 2013; 32: 4549–56.
- 3Warburg O. On the origin of cancer cells. Science 1956; 123: 309–14.
- 4Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol 1927; 8: 519–30.
- 5Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008; 452: 230–3.
- 6Noh S, Kim do H, Jung WH, Koo JS. Expression levels of serine/glycine metabolism-related proteins in triple negative breast cancer tissues. Tumour Biol 2014; 35: 4457–68.
- 7Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 2011; 476: 346–50.
- 8Youngblood B, Shieh FK, Buller F, Bullock T, Reich NO. S-adenosyl-L-methionine-dependent methyl transfer: observable precatalytic intermediates during DNA cytosine methylation. Biochemistry 2007; 46: 8766–75.
- 9Ham MS, Lee JK, Kim KC. S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells. Mol Clin Oncol 2013; 1: 373–8.
- 10Detich N, Hamm S, Just G, Knox JD, Szyf M. The methyl donor S-Adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-Adenosylmethionine. J Biol Chem 2003; 278: 20812–20.
- 11Basurko MJ, Marche M, Darriet M, Cassaigne A. Phosphoserine aminotransferase, the second step-catalyzing enzyme for serine biosynthesis. IUBMB Life 1999; 48: 525–9.
- 12Tsukada Y, Fang J, Erdjument-Bromage H, Warren ME, Borchers CH, Tempst P et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 2006; 439: 811–6.
- 13Coffey K, Rogerson L, Ryan-Munden C, Alkharaif D, Stockley J, Heer R et al. The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover. Nucleic Acids Res 2013; 41: 4433–46.
- 14Yamane K, Toumazou C, Tsukada Y, Erdjument-Bromage H, Tempst P, Wong J et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 2006; 125: 483–95.
- 15Mahajan K, Lawrence HR, Lawrence NJ, Mahajan NP. ACK1 Tyrosine Kinase Interacts with Histone Demethylase KDM3A to Regulate the Mammary Tumor Oncogene HOXA1. J Biol Chem 2014; 289: 28179–91.
- 16Gaughan L, Stockley J, Coffey K, O'Neill D, Jones DL, Wade M et al. KDM4B is a master regulator of the estrogen receptor signalling cascade. Nucleic Acids Res 2013; 41: 6892–904.
- 17Forma E, Jozwiak P, Brys M, Krzeslak A. The potential role of O-GlcNAc modification in cancer epigenetics. Cell Mol Biol Lett 2014; 19: 438–60.
- 18Hardiville S, Hart GW. Nutrient Regulation of Signaling, Transcription, and Cell Physiology by O-GlcNAcylation. Cell Metab 2014; 20: 208–13.
- 19Paterson AJ, Kudlow JE. Regulation of glutamine:fructose-6-phosphate amidotransferase gene transcription by epidermal growth factor and glucose. Endocrinology 1995; 136: 2809–16.
- 20Manzari B, Kudlow JE, Fardin P, Merello E, Ottaviano C, Puppo M et al. Induction of macrophage glutamine: fructose-6-phosphate amidotransferase expression by hypoxia and by picolinic acid. Int J Immunopathol Pharmacol 2007; 20: 47–58.
- 21Roskoski R Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 2014; 79: 34–74.
- 22Zeng W, Liu P, Pan W, Singh SR, Wei Y. Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett 2014 Feb 4. pii: S0304-3835(14)00089-5
- 23Gu Y, Mi W, Ge Y, Liu H, Fan Q, Han C et al. GlcNAcylation plays an essential role in breast cancer metastasis. Cancer Res 2010; 70: 6344–51.
- 24Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ. Critical role of O-Linked beta-N-acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem 2012; 287: 11070–81.
- 25Olivier-Van Stichelen S, Drougat L, Dehennaut V, El Yazidi-Belkoura I, Guinez C, Mir AM et al. Serum-stimulated cell cycle entry promotes ncOGT synthesis required for cyclin D expression. Oncogenesis 2012; 1: e36.
- 26Olivier-Van Stichelen S, Guinez C, Mir AM, Perez-Cervera Y, Liu C, Michalski JC et al. The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of beta-catenin and cell proliferation. Am J Physiol Endocrinol Metab 2012; 302: E417–24.
- 27Lin HC, Kachingwe BH, Lin HL, Cheng HW, Uang YS, Wang LH. Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study. Pharmacotherapy 2014; 34: 36–45.
- 28Salani B, Marini C, Rio AD, Ravera S, Massollo M, Orengo AM et al. Metformin impairs glucose consumption and survival in Calu-1 cells by direct inhibition of hexokinase-II. Sci Rep 2013; 3: 2070.
- 29Sakabe K, Wang Z, Hart GW. Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc Natl Acad Sci USA 2010; 107: 19915–20.
- 30Bullen JW, Balsbaugh JL, Chanda D, Shabanowitz J, Hunt DF, Neumann D et al. Cross-talk between two essential nutrient-sensitive enzymes: O-GlcNAc transferase (OGT) and AMP-activated protein kinase (AMPK). J Biol Chem 2014; 289: 10592–606.
- 31Xu Q, Yang C, Du Y, Chen Y, Liu H, Deng M et al. AMPK regulates histone H2B O-GlcNAcylation. Nucleic Acids Res 2014; 42: 5594–604.
- 32Ito R, Katsura S, Shimada H, Tsuchiya H, Hada M, Okumura T et al. TET3-OGT interaction increases the stability and the presence of OGT in chromatin. Genes Cells 2014; 19: 52–65.
- 33Zhang Q, Liu X, Gao W, Li P, Hou J, Li J et al. Differential regulation of the ten-eleven translocation (TET) family of dioxygenases by O-linked beta-N-acetylglucosamine transferase (OGT). J Biol Chem 2014; 289: 5986–96.
- 34Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J Clin Invest 2013; 123: 3678–84.
- 35He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011; 333: 1303–7.
- 36Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 2009; 41: 838–42.
- 37Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 2003; 17: 637–41.
- 38Haseeb A, Makki MS, Haqqi TM. Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, alpha-Ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes. J Biol Chem 2014; 289: 6877–85.
- 39Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848–51.
- 40Gimm O, Armanios M, Dziema H, Neumann HP, Eng C. Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res 2000; 60: 6822–5.
- 41Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005; 7: 77–85.
- 42Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12: 1241–52.
- 43Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002; 30: 406–10.
- 44Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005; 8: 143–53.
- 45Mason EF, Hornick JL. Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis. Mod Pathol 2013; 26: 1492–7.
- 46Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 2012; 26: 1326–38.
- 47Smith EH, Janknecht R, Maher LJ 3rd. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum Mol Genet 2007; 16: 3136–48.
- 48Berry WL, Kim TD, Janknecht R. Stimulation of beta-catenin and colon cancer cell growth by the KDM4B histone demethylase. Int J Oncol 2014; 44: 1341–8.
- 49Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008; 321: 1807–12.
- 50Yan H, Bigner DD, Velculescu V, Parsons DW. Mutant metabolic enzymes are at the origin of gliomas. Cancer Res 2009; 69: 9157–9.
- 51Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462: 739–44.
- 52Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17: 225–34.
- 53Losman JA, Kaelin WG Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 2013; 27: 836–52.
- 54Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 2011; 19: 17–30.
- 55Casalino L, Comes S, Lambazzi G, De Stefano B, Filosa S, De Falco S et al. Control of embryonic stem cell metastability by L-proline catabolism. J Mol Cell Biol 2011; 3: 108–22.
- 56Washington JM, Rathjen J, Felquer F, Lonic A, Bettess MD, Hamra N et al. L-Proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture. Am J Physiol Cell Physiol 2010; 298: C982–92.
- 57Zarse K, Schmeisser S, Groth M, Priebe S, Beuster G, Kuhlow D et al. Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal. Cell Metab 2012; 15: 451–65.
- 58Boyd-Kirkup JD, Green CD, Wu G, Wang D, Han JD. Epigenomics and the regulation of aging. Epigenomics 2013; 5: 205–27.
- 59Papp B, Plath K. Epigenetics of reprogramming to induced pluripotency. Cell 2013; 152: 1324–43.
- 60Liu Y, Borchert GL, Donald SP, Diwan BA, Anver M, Phang JM. Proline oxidase functions as a mitochondrial tumor suppressor in human cancers. Cancer Res 2009; 69: 6414–22.
- 61Liu Y, Borchert GL, Surazynski A, Hu CA, Phang JM. Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. Oncogene 2006; 25: 5640–7.
- 62Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW et al. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 2012; 109: 8983–8.
- 63Coulter JB, O'Driscoll CM, Bressler JP. Hydroquinone increases 5-hydroxymethylcytosine formation through ten eleven translocation 1 (TET1) 5-methylcytosine dioxygenase. J Biol Chem 2013; 288: 28792–800.
- 64Tanner JJ. Structural biology of proline catabolism. Amino Acids 2008; 35: 719–30.
- 65Phang JM, Liu W, Hancock C. Bridging epigenetics and metabolism: role of non-essential amino acids. Epigenetics 2013; 8: 231–6.
- 66Salani B, Del Rio A, Marini C, Sambuceti G, Cordera R, Maggi DC. Metformin, cancer and glucose metabolism. Endocr Relat Cancer 2014; 21: 461–71.
