The histone code is regulated by epigenetic 'readers', 'writers' and 'erasers'. This Review proposes adding to this paradigm the availability of the 'ink' needed to pen chromatin modifications, with the ink being metabolites that are substrates of chromatin-modifying enzymes (that is, for example, acetyl-CoA is the ink for acetyltransferases).
This Review puts forward a three-model framework by which metabolism can regulate the epigenome: inhibitor metabolite production; nutrient sensing and chromatin regulation; and localized metabolite production.
Metabolic and epigenetic changes are both common features found in all cancer types. Metabolic rewiring in cancer cells provides advantages not only through direct metabolic functions, but also by acting on the epigenetic landscape.
Cell signalling has long been known to affect nutrient uptake and use. However, metabolism also feeds back onto signalling pathways to play an active part in major cellular decisions, such as proliferation or differentiation. This reciprocal feedback between cell signalling and metabolism is manipulated in cancer cells to provide growth and survival advantages.
Improved understanding of the interplay between cell metabolism and the epigenome will be crucial in designing novel cancer therapeutic strategies.
Alterations in the epigenome and metabolism both affect molecular rewiring in cancer cells and facilitate cancer development and progression. However, recent evidence suggests the existence of important bidirectional regulatory mechanisms between metabolic remodelling and the epigenome (specifically methylation and acetylation of histones) in cancer. Most chromatin-modifying enzymes require substrates or cofactors that are intermediates of cell metabolism. Such metabolites, and often the enzymes that produce them, can transfer into the nucleus, directly linking metabolism to nuclear transcription. We discuss how metabolic remodelling can contribute to tumour epigenetic alterations, thereby affecting cancer cell differentiation, proliferation and/or apoptosis, as well as therapeutic responses.
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Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).
Wellen, K. E. & Thompson, C. B. A two-way street: reciprocal regulation of metabolism and signalling. Nat. Rev. Mol. Cell Biol. 13, 270–276 (2012).
Kinnaird, A. & Michelakis, E. D. Metabolic modulation of cancer: a new frontier with great translational potential. J. Mol. Med. (Berl.) 93, 127–142 (2015).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000). This paper defined the 'histone code,' altering the way we think about and discuss histone PTMs.
Chen, Y. et al. Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol. Cell. Proteom. 11, 1048–1062 (2012).
Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009). This paper used high-resolution mass spectrometry to show that protein acetylation is a common PTM on thousands of proteins throughout the cell.
Scholz, C. et al. Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat. Biotechnol. 33, 415–423 (2015).
Pietrocola, F., Galluzzi, L., Bravo- San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).
Huang, H., Sabari, B. R., Garcia, B. A., Allis, C. D. & Zhao, Y. SnapShot: histone modifications. Cell 159, 458–458 (2014).
Huang, H., Lin, S., Garcia, B. A. & Zhao, Y. Quantitative proteomic analysis of histone modifications. Chem. Rev. 115, 2376–2418 (2015).
Polevoda, B. & Sherman, F. Nα-terminal acetylation of eukaryotic proteins. J. Biol. Chem. 275, 36479–36482 (2000).
Hollebeke, J., Van Damme, P. & Gevaert, K. N-Terminal acetylation and other functions of Nα-acetyltransferases. Biol. Chem. 393, 291–298 (2012).
Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014).
Dhalluin, C. et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491–496 (1999).
Zeng, L. & Zhou, M. M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124–128 (2002).
Wagner, G. R. & Hirschey, M. D. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol. Cell 54, 5–16 (2014).
Olia, A. S. et al. Nonenzymatic protein acetylation detected by NAPPA protein arrays. ACS Chem. Biol. 10, 2034–2047 (2015).
Bonnet, S. et al. A mitochondria–K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007).
Chen, L. B. Mitochondrial membrane potential in living cells. Annu. Rev. Cell Biol. 4, 155–181 (1988).
Wagner, G. R. & Payne, R. M. Widespread and enzyme-independent Nε-acetylation and Nε-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J. Biol. Chem. 288, 29036–29045 (2013).
McBrian, M. A. et al. Histone acetylation regulates intracellular pH. Mol. Cell 49, 310–321 (2013).
Seligson, D. B. et al. Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol. 174, 1619–1628 (2009).
Seligson, D. B. et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262–1266 (2005).
Elsheikh, S. E. et al. Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res. 69, 3802–3809 (2009).
Mosashvilli, D. et al. Global histone acetylation levels: prognostic relevance in patients with renal cell carcinoma. Cancer Sci. 101, 2664–2669 (2010).
Tzao, C. et al. Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus. Mod. Pathol. 22, 252–260 (2009).
I, H. et al. Association of global levels of histone modifications with recurrence-free survival in stage IIB and III esophageal squamous cell carcinomas. Cancer Epidemiol. Biomarkers Prev. 19, 566–573 (2010).
Jencks, W. P. Handbook of Biochemistry and Molecular Biology (CRC Press, 1976).
Nelson, D. & Cox, M. M. Lehninger Principles of Biochemistry (W. H. Freeman and Company, 2013).
Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983).
Herman, J. G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA 91, 9700–9704 (1994).
Greger, V., Passarge, E., Hopping, W., Messmer, E. & Horsthemke, B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83, 155–158 (1989).
Esteller, M. et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564–569 (2000).
Bachman, K. E. et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89–95 (2003).
Albert, M. & Helin, K. Histone methyltransferases in cancer. Semin. Cell Dev. Biol. 21, 209–220 (2010).
Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).
Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).
Vousden, K. Serine metabolism and the methionine cycle. Nat Rev Cancer https://dx.doi.org/10.1038/nrc.2016.81 (2016).
Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).
Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).
Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012). This study identified that succinate and fumarate are competitive inhibitors of α-KG-dependent dioxygenases, resulting in impaired histone demethylation and 5-methylcytosine hydroxylation in the context of SDH and FH mutation in cancer.
Killian, J. K. et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 3, 648–657 (2013).
Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).
Lee, J. V. et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306–319 (2014). This study identified that oncogenic AKT-dependent metabolic rewiring drives ACLY-dependent acetyl-CoA production and histone acetylation in cancer.
Albaugh, B. N., Arnold, K. M. & Denu, J. M. KAT(ching) metabolism by the tail: insight into the links between lysine acetyltransferases and metabolism. Chembiochem 12, 290–298 (2011).
Meier, J. L. Metabolic mechanisms of epigenetic regulation. ACS Chem. Biol. 8, 2607–2621 (2013).
Montgomery, D. C., Sorum, A. W., Guasch, L., Nicklaus, M. C. & Meier, J. L. Metabolic regulation of histone acetyltransferases by endogenous acyl-CoA cofactors. Chem. Biol. 22, 1030–1039 (2015).
Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).
Latham, T. et al. Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acids Res. 40, 4794–4803 (2012).
Shimazu, T. et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214 (2013).
Cluntun, A. A. et al. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab. 3, 10 (2015).
Dromparis, P. & Michelakis, E. D. Mitochondria in vascular health and disease. Annu. Rev. Physiol. 75, 95–126 (2013).
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009). This paper was the first to show that acetyl-CoA derived from nutrient metabolism is used to alter histone acetylation and gene expression in mammalian cells.
Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).
Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).
Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012).
Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591–1602 (2014).
Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014).
Kamphorst, J. J., Chung, M. K., Fan, J. & Rabinowitz, J. D. Quantitative analysis of acetyl-CoA production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer Metab. 2, 23 (2014).
Schug, Z. T. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015).
Takahashi, H., McCaffery, J. M., Irizarry, R. A. & Boeke, J. D. Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription. Mol. Cell 23, 207–217 (2006). This paper was the first to show that acetyl-CoA derived from acetate metabolism is used by acetyltransferases to alter histone acetylation in yeast.
Chen, R. et al. The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PLoS ONE 10, e0116515 (2015).
Sutendra, G. et al. A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 158, 84–97 (2014). This study identified that PDC can translocate from mitochondria to the nucleus in response to growth factor signalling or mitochondrial stress, to enable generation of acetyl-CoA from pyruvate for histone acetylation.
Xu, M. et al. An acetate switch regulates stress erythropoiesis. Nat. Med. 20, 1018–1026 (2014).
Martinez-Reyes, I. et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 61, 199–209 (2015).
Dang, C. V. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb. Perspect. Med. 3, a014217 (2013).
Dang, C. V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell. Biol. 19, 1–11 (1999).
Whiteman, E. L., Cho, H. & Birnbaum, M. J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444–451 (2002).
Morrish, F. et al. Myc-dependent mitochondrial generation of acetyl-CoA contributes to fatty acid biosynthesis and histone acetylation during cell cycle entry. J. Biol. Chem. 285, 36267–36274 (2010).
Edmunds, L. R. et al. c-Myc programs fatty acid metabolism and dictates acetyl-CoA abundance and fate. J. Biol. Chem. 289, 25382–25392 (2014).
Morrish, F., Isern, N., Sadilek, M., Jeffrey, M. & Hockenbery, D. M. c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene 28, 2485–2491 (2009).
Berwick, D. C., Hers, I., Heesom, K. J., Moule, S. K. & Tavare, J. M. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem. 277, 33895–33900 (2002).
Potapova, I. A., El-Maghrabi, M. R., Doronin, S. V. & Benjamin, W. B. Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars. Biochemistry 39, 1169–1179 (2000).
Hitosugi, T. et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell 44, 864–877 (2011).
Fan, J. et al. Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol. Cell 53, 534–548 (2014).
Fan, J. et al. Tyr-301 phosphorylation inhibits pyruvate dehydrogenase by blocking substrate binding and promotes the Warburg effect. J. Biol. Chem. 289, 26533–26541 (2014).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Ward, P. S. 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 17, 225–234 (2010). References 80 and 82 identified that mutations in IDH1 and IDH2 result in the production of 2-HG in cancer.
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013).
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010). This paper elucidated the mechanism linking oncometabolite production and a hypermethylated DNA phenotype in cancer cells.
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Cairns, R. A. & Mak, T. W. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 3, 730–741 (2013).
Intlekofer, A. M. et al. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015).
Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in L-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015).
Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).
Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).
Mihaylova, M. M. & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016–1023 (2011).
Bungard, D. et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201–1205 (2010).
Mudd, S. H. & Poole, J. R. Labile methyl balances for normal humans on various dietary regimens. Metabolism 24, 721–735 (1975).
Poirier, L. A., Wise, C. K., Delongchamp, R. R. & Sinha, R. Blood determinations of S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine: correlations with diet. Cancer Epidemiol. Biomarkers Prev. 10, 649–655 (2001).
Lim, U. & Song, M. A. Dietary and lifestyle factors of DNA methylation. Methods Mol. Biol. 863, 359–376 (2012).
Pufulete, M. et al. Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54, 648–653 (2005).
Cravo, M. L. et al. Effect of folate supplementation on DNA methylation of rectal mucosa in patients with colonic adenomas: correlation with nutrient intake. Clin. Nutr. 17, 45–49 (1998).
Schernhammer, E. S. et al. Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer. Gut 59, 794–799 (2010).
Kadaveru, K., Protiva, P., Greenspan, E. J., Kim, Y. I. & Rosenberg, D. W. Dietary methyl donor depletion protects against intestinal tumorigenesis in Apc(Min/+) mice. Cancer Prev. Res. (Phila) 5, 911–920 (2012).
Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015). This study showed that methionine availability affects levels of the methyl donor SAM, regulating histone methylation levels in cultured cells and in tissues in vivo.
Cai, L., Sutter, B. M., Li, B. & Tu, B. P. Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes. Mol. Cell 42, 426–437 (2011). This study showed that metabolically derived acetyl-CoA is used to coordinate a gene expression programme used to promote cellular growth.
Donohoe, D. R. et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol. Cell 48, 612–626 (2012). This study provided insight into the 'butyrate paradox', by showing that in the absence of the Warburg effect, colonocytes oxidize butyrate for acetyl-CoA production, promoting histone acetylation and cell proliferation. However, in glycolytic colon cancer cells, butyrate accumulates in the nucleus and acts as a KDAC inhibitor, resulting in elevated histone acetylation but inhibition of proliferation.
Shi, L. & Tu, B. P. Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 110, 7318–7323 (2013).
Henry, R. A., Kuo, Y. M., Bhattacharjee, V., Yen, T. J. & Andrews, A. J. Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation. ACS Chem. Biol. 10, 146–156 (2015).
Denisov, I. G. & Sligar, S. G. A novel type of allosteric regulation: functional cooperativity in monomeric proteins. Arch. Biochem. Biophys. 519, 91–102 (2012).
Gao, L. et al. Simultaneous quantification of malonyl-CoA and several other short-chain acyl-CoAs in animal tissues by ion-pairing reversed-phase HPLC/MS. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 853, 303–313 (2007).
Katoh, Y. et al. Methionine adenosyltransferase II serves as a transcriptional corepressor of Maf oncoprotein. Mol. Cell 41, 554–566 (2011).
Kera, Y. et al. Methionine adenosyltransferase II-dependent histone H3K9 methylation at the COX-2 gene locus. J. Biol. Chem. 288, 13592–13601 (2013).
Matsuda, S. et al. Nuclear pyruvate kinase M2 complex serves as a transcriptional coactivator of arylhydrocarbon receptor. Nucleic Acids Res. 44, 636–647 (2015).
Li, S. et al. Serine and SAM responsive complex SESAME regulates histone modification crosstalk by sensing cellular metabolism. Mol. Cell 60, 408–421 (2015).
Jiang, Y. et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat. Cell Biol. 17, 1158–1168 (2015).
Moussaieff, A. et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 21, 392–402 (2015).
Wang, J. et al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 325, 435–439 (2009).
Eisenberg, T. et al. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab. 19, 431–444 (2014).
Marino, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).
Peng, Y. et al. Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer. J. Neurosci. 34, 6772–6789 (2014).
Yi, C. H. et al. Metabolic regulation of protein N-α-acetylation by Bcl-xL promotes cell survival. Cell 146, 607–620 (2011).
Peleg, S. et al. Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. EMBO Rep. 17, 455–469 (2016).
Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).
Shiraki, N. et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab. 19, 780–794 (2014).
Sperber, H. et al. The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat. Cell Biol. 17, 1523–1535 (2015).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). This study demonstrated that 2-HG production by mutant IDH inhibits histone demethylation, resulting in H3K9 and H3K27 hypermethylation and inhibition of cellular differentiation.
Saha, S. K. et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513, 110–114 (2014).
Lu, C. et al. Induction of sarcomas by mutant IDH2. Genes Dev. 27, 1986–1998 (2013).
Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).
Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).
Turcan, S. et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget 4, 1729–1736 (2013).
Borodovsky, A. et al. 5-Azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget 4, 1737–1747 (2013).
Flavahan, W. A. et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110–114 (2016). This paper showed that altered metabolism (due to IDH mutation) in cancer may facilitate oncogene expression owing to changes in the 3D structure of chromatin.
Katainen, R. et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat. Genet. 47, 818–821 (2015).
Ji, X. et al. 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell 18, 262–275 (2016).
Hnisz, D. et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454–1458 (2016).
Kim, H. S. et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell 17, 41–52 (2010).
Paulin, R. et al. Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab. 20, 827–839 (2014).
Finley, L. W. et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416–428 (2011).
Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010).
Bharathi, S. S. et al. Sirtuin 3 (SIRT3) protein regulates long-chain acyl-CoA dehydrogenase by deacetylating conserved lysines near the active site. J. Biol. Chem. 288, 33837–33847 (2013).
Yu, W., Dittenhafer-Reed, K. E. & Denu, J. M. SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status. J. Biol. Chem. 287, 14078–14086 (2012).
Finley, L. W. et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS ONE 6, e23295 (2011).
Cimen, H. et al. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49, 304–311 (2010).
Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008).
Tao, R. et al. Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 40, 893–904 (2010).
Lim, J. H. et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol. Cell 38, 864–878 (2010).
Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006).
Izumi, H. et al. p300/CBP-associated factor (P/CAF) interacts with nuclear respiratory factor-1 to regulate the UDP-N-acetyl-α-d-galactosamine: polypeptide N-acetylgalactosaminyltransferase-3 gene. Biochem. J. 373, 713–722 (2003).
Lerin, C. et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1α. Cell Metab. 3, 429–438 (2006).
Keith, B., Johnson, R. S. & Simon, M. C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat. Rev. Cancer 12, 9–22 (2012).
Li, T. et al. Glyceraldehyde-3-phosphate dehydrogenase is activated by lysine 254 acetylation in response to glucose signal. J. Biol. Chem. 289, 3775–3785 (2014).
Ventura, M. et al. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase is regulated by acetylation. Int. J. Biochem. Cell Biol. 42, 1672–1680 (2010).
Lv, L. et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol. Cell 52, 340–352 (2013).
Vervoorts, J. et al. Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep. 4, 484–490 (2003).
Faiola, F. et al. Dual regulation of c-Myc by p300 via acetylation-dependent control of Myc protein turnover and coactivation of Myc-induced transcription. Mol. Cell. Biol. 25, 10220–10234 (2005).
Patel, J. H. et al. The c-MYC oncoprotein is a substrate of the acetyltransferases hGCN5/PCAF and TIP60. Mol. Cell. Biol. 24, 10826–10834 (2004).
Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).
Masui, K. et al. Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. Proc. Natl Acad. Sci. USA 112, 9406–9411 (2015).
Shan, C. et al. Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol. Cell 55, 552–565 (2014).
Patra, K. C. & Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 39, 347–354 (2014).
Lin, R. et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol. Cell 51, 506–518 (2014).
Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).
Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).
Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).
Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016). References 161–163 showed that MTAP is frequently deleted as a consequence of 9p21 loss, leading to deregulated methionine metabolism and sensitization to inhibition of PRMT5.
Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).
Pearce, N. J. et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem. J. 334, 113–119 (1998).
Li, J. J. et al. 2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg. Med. Chem. Lett. 17, 3208–3211 (2007).
Gutierrez, M. J. et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 34, 676–683 (2014).
Filippov, S., Pinkosky, S. L. & Newton, R. S. LDL-cholesterol reduction in patients with hypercholesterolemia by modulation of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase. Curr. Opin. Lipidol. 25, 309–315 (2014).
Ballantyne, C. M. et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J. Am. Coll. Cardiol. 62, 1154–1162 (2013).
Madeo, F., Pietrocola, F., Eisenberg, T. & Kroemer, G. Caloric restriction mimetics: towards a molecular definition. Nat. Rev. Drug Discov. 13, 727–740 (2014).
Onakpoya, I., Hung, S. K., Perry, R., Wider, B. & Ernst, E. The use of garcinia extract (hydroxycitric acid) as a weight loss supplement: a systematic review and meta-analysis of randomised clinical trials. J. Obes. 2011, 509038 (2011).
Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl Med. 2, 31ra34 (2010).
Chu, Q. S. et al. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Invest. New Drugs 33, 603–610 (2015).
Dunbar, E. M. et al. Phase 1 trial of dichloroacetate (DCA) in adults with recurrent malignant brain tumors. Invest. New Drugs 32, 452–464 (2014).
Shan, C. et al. Tyr-94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J. Biol. Chem. 289, 21413–21422 (2014).
Falkenberg, K. J. & Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673–691 (2014).
Bantscheff, M. et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29, 255–265 (2011).
West, A. C. & Johnstone, R. W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124, 30–39 (2014).
Eckel-Mahan, K. & Sassone-Corsi, P. Metabolism and the circadian clock converge. Physiol. Rev. 93, 107–135 (2013).
Sahar, S. et al. Circadian control of fatty acid elongation by SIRT1 protein-mediated deacetylation of acetyl-coenzyme A synthetase 1. J. Biol. Chem. 289, 6091–6097 (2014).
Chow, J. D. et al. Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation. Mol. Metab. 3, 419–431 (2014).
Cahill, G. F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).
Cederbaum, A. I. Alcohol metabolism. Clin. Liver Dis. 16, 667–685 (2012).
Gao, X. et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat. Commun. 7, 11960 (2016).
The authors declare no competing financial interests.
Enzymes responsible for adding a post-translational modification, such as acetyltransferases and methyltransferases.
Enzymes responsible for removing post-translational modification, such as deacetylases and demethylases.
Proteins the activity of which changes based on the presence of a post-translational modification.
- Nα acetyltransferases
Acetyltransferases that carry out cotranslational acetylation of an amino acid at the N-terminus of a protein.
- Nε acetylation
Post-translational acetylation of the ε-amino group of a lysine residue, catalysed by lysine acetyltransferases (KATs).
- CpG islands
Clusters of cytosine-phosphate- guanine dinucleotides in a higher quantity than randomly expected.
- Methionine cycle
An essential pathway in one-carbon metabolism that generates the methyl donor S-adenosylmethionine (SAM).
Addition of a crotonyl group (from crotonyl-CoA) to a lysine residue, catalysed by a crotonyltransferase.
- Reductive carboxylation of glutamine
A metabolic process (also called the reductive glutamine pathway) that generates both cytoplasmic and mitochondrial metabolites, such as citrate, from glutamine.
- Topologically associating domains
(TADs). The organization of chromatin into spatially discrete 3D structures (also called neighbourhoods) that regulate local gene expression.
- Pulmonary arterial hypertension
A vascular remodelling disease characterized by a pro-proliferative and anti-apoptotic environment in the pulmonary arterial wall, resulting in excessive proliferation and obliteration of the vascular lumen; like cancer, it is characterized by mitochondrial suppression (in all the cells of the vascular wall).
- Pentose phosphate pathway
(PPP). An anabolic pathway designed for the synthesis of ribonucleotides and the production of NADPH.
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Kinnaird, A., Zhao, S., Wellen, K. et al. Metabolic control of epigenetics in cancer. Nat Rev Cancer 16, 694–707 (2016). https://doi.org/10.1038/nrc.2016.82
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