Metabolic control of epigenetics in cancer

Nature Reviews Cancer

Volumn 16, Issue 11, 2016, Pages 694-707

  Kinnaird, Adam ^a   Zhao, Steven ^b   Wellen, Kathryn E ^b   Michelakis, Evangelos D ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYL COENZYME A;

ACETYLATION; APOPTOSIS; BIOCHEMISTRY; CANCER CELL; CANCER GENETICS; CELL DIFFERENTIATION; CELL METABOLISM; CELL PROLIFERATION; CELLULAR DISTRIBUTION; CHOREOGRAPHY; CHROMATIN; ENZYME INHIBITION; ENZYME METABOLISM; EPIGENETICS; METABOLIC REGULATION; METABOLITE; METHYLATION; ONCOGENE; PRIORITY JOURNAL; REVIEW; CELLS; DNA METHYLATION; GENETIC EPIGENESIS; GENETICS; HUMAN; METABOLISM; NEOPLASM; PHYSIOLOGY;

ACETYLATION; CELLS; DNA METHYLATION; EPIGENESIS, GENETIC; HUMANS; NEOPLASMS;

EID: 84988345850     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc.2016.82     Document Type: Review

References (184)

1. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148-1159 (2008
2. Hanahan, D., & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011
3. 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
4. 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
5. Kinnaird, A., & Michelakis, E. D. Metabolic modulation of cancer: a new frontier with great translational potential. J. Mol. Med. (Berl.) 93, 127-142 (2015
6. Strahl, B. D., & Allis, C. D. The language of covalent histone modifications. Nature 403, 41-45 (2000
7. 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
8. Choudhary, C., et al. Lysine acetylation targets protein complexes and co regulates major cellular functions. Science 325, 834-840 (2009
9. Scholz, C., et al. Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat. Biotechnol. 33, 415-423 (2015
10. 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
11. Huang, H., Sabari, B. R., Garcia, B. A., Allis, C. D., & Zhao, Y. SnapShot: histone modifications. Cell 159, 458-458 (2014
12. Huang, H., Lin, S., Garcia, B. A., & Zhao, Y. Quantitative proteomic analysis of histone modifications. Chem. Rev. 115, 2376-2418 (2015
13. Polevoda, B., & Sherman, F. Nα-terminal acetylation of eukaryotic proteins. J. Biol. Chem. 275, 36479-36482 (2000
14. Hollebeke, J., Van Damme, P., & Gevaert, K. N Terminal acetylation and other functions of Nα-acetyltransferases. Biol. Chem. 393, 291-298 (2012
15. 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
16. Dhalluin, C., et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491-496 (1999
17. Zeng, L., & Zhou, M. M. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 513, 124-128 (2002
18. Wagner, G. R., & Hirschey, M. D. Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol. Cell 54, 5-16 (2014
19. Olia, A. S., et al. Nonenzymatic protein acetylation detected by NAPPA protein arrays. ACS Chem. Biol. 10, 2034-2047 (2015
20. 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
21. Chen, L. B. Mitochondrial membrane potential in living cells. Annu. Rev. Cell Biol. 4, 155-181 (1988
22. 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
23. McBrian, M. A., et al. Histone acetylation regulates intracellular pH. Mol. Cell 49, 310-321 (2013
24. Seligson, D. B., et al. Global levels of histone modifications predict prognosis in different cancers. Am. J. Pathol. 174, 1619-1628 (2009
25. Seligson, D. B., et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435, 1262-1266 (2005
26. 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
27. Mosashvilli, D., et al. Global histone acetylation levels: prognostic relevance in patients with renal cell carcinoma. Cancer Sci. 101, 2664-2669 (2010
28. Tzao, C., et al. Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus. Mod. Pathol. 22, 252-260 (2009
29. 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
30. Jencks, W. P. Handbook of Biochemistry and Molecular Biology (CRC Press, 1976
31. Nelson, D., & Cox, M. M. Lehninger Principles of Biochemistry (W. H. Freeman and Company, 2013
32. Feinberg, A. P., & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89-92 (1983
33. 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
34. 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
35. Esteller, M., et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564-569 (2000
36. Bachman, K. E., et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89-95 (2003
37. Albert, M., & Helin, K. Histone methyltransferases in cancer. Semin. Cell Dev. Biol. 21, 209-220 (2010
38. Shi, Y., et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953 (2004
39. Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572-583 (2013
40. Vousden, K. Serine metabolism and the methionine cycle. Nat Rev Cancer https://dx.doi.org/10.1038/nrc.2016.81 (2016
41. 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
42. Tsukada, Y., et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811-816 (2006
43. 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
44. Killian, J. K., et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 3, 648-657 (2013
45. 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
46. Lee, J. V., et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 20, 306-319 (2014
47. 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
48. Meier, J. L. Metabolic mechanisms of epigenetic regulation. ACS Chem. Biol. 8, 2607-2621 (2013
49. 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
50. Sabari, B. R., et al. Intracellular crotonyl-CoA stimulates transcription through p300 catalyzed histone crotonylation. Mol. Cell 58, 203-215 (2015
51. Houtkooper, R. H., Pirinen, E., & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225-238 (2012
52. 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
53. Shimazu, T., et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211-214 (2013
54. Cluntun, A. A., et al. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab. 3, 10 (2015
55. Dromparis, P., & Michelakis, E. D. Mitochondria in vascular health and disease. Annu. Rev. Physiol. 75, 95-126 (2013
56. Wellen, K. E., et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076-1080 (2009
57. 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
58. Metallo, C. M., et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380-384 (2012
59. Mullen, A. R., et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385-388 (2012
60. Comerford, S. A., et al. Acetate dependence of tumors. Cell 159, 1591-1602 (2014
61. Mashimo, T., et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-1614 (2014
62. 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
63. 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
64. 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
65. Chen, R., et al. The acetate/ACSS2 switch regulates HIF 2 stress signaling in the tumor cell microenvironment. PLoS ONE 10, e0116515 (2015
66. 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
67. Xu, M., et al. An acetate switch regulates stress erythropoiesis. Nat. Med. 20, 1018-1026 (2014
68. Martinez-Reyes, I., et al. TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol. Cell 61, 199-209 (2015
69. Dang, C. V. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb. Perspect. Med. 3, a014217 (2013
70. Dang, C. V. c Myc target genes involved in cell growth, apoptosis, and metabolism. Mol. Cell. Biol. 19, 1-11 (1999
71. Whiteman, E. L., Cho, H., & Birnbaum, M. J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444-451 (2002
72. 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
73. 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
74. 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
75. 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
76. 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
77. Hitosugi, T., et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell 44, 864-877 (2011
78. 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
79. 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
80. Dang, L., et al. Cancer-associated IDH1 mutations produce 2 hydroxyglutarate. Nature 462, 739-744 (2009
81. Yan, H., et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773 (2009
82. 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
83. Parsons, D. W., et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807-1812 (2008
84. Losman, J. A., et al. (R)-2 hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621-1625 (2013
85. 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
86. Xu, W., et al. Oncometabolite 2 hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17-30 (2011
87. Cairns, R. A., & Mak, T. W. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 3, 730-741 (2013
88. Intlekofer, A. M., et al. Hypoxia induces production of L-2 hydroxyglutarate. Cell Metab. 22, 304-311 (2015
89. 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
90. Letouze, E., et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739-752 (2013
91. 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
92. Mihaylova, M. M., & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016-1023 (2011
93. Bungard, D., et al. Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201-1205 (2010
94. Mudd, S. H., & Poole, J. R. Labile methyl balances for normal humans on various dietary regimens. Metabolism 24, 721-735 (1975
95. 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
96. Lim, U., & Song, M. A. Dietary and lifestyle factors of DNA methylation. Methods Mol. Biol. 863, 359-376 (2012
97. Pufulete, M., et al. Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54, 648-653 (2005
98. 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
99. 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
100. 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
101. 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
102. 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
103. 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
104. 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
105. 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
106. Denisov, I. G., & Sligar, S. G. A novel type of allosteric regulation: functional cooperativity in monomeric proteins. Arch. Biochem. Biophys. 519, 91-102 (2012
107. 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
108. Katoh, Y., et al. Methionine adenosyltransferase II serves as a transcriptional corepressor of Maf oncoprotein. Mol. Cell 41, 554-566 (2011
109. Kera, Y., et al. Methionine adenosyltransferase II dependent histone H3K9 methylation at the COX 2 gene locus. J. Biol. Chem. 288, 13592-13601 (2013
110. Matsuda, S., et al. Nuclear pyruvate kinase M2 complex serves as a transcriptional coactivator of arylhydrocarbon receptor. Nucleic Acids Res. 44, 636-647 (2015
111. Li, S., et al. Serine and SAM responsive complex SESAME regulates histone modification crosstalk by sensing cellular metabolism. Mol. Cell 60, 408-421 (2015
112. Jiang, Y., et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat. Cell Biol. 17, 1158-1168 (2015
113. 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
114. Wang, J., et al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 325, 435-439 (2009
115. Eisenberg, T., et al. Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab. 19, 431-444 (2014
116. Marino, G., et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710-725 (2014
117. 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
118. Yi, C. H., et al. Metabolic regulation of protein N α-acetylation by Bcl xL promotes cell survival. Cell 146, 607-620 (2011
119. Peleg, S., et al. Life span extension by targeting a link between metabolism and histone acetylation in Drosophila. EMBO Rep. 17, 455-469 (2016
120. Shyh-Chang, N., et al. Influence of threonine metabolism on S adenosylmethionine and histone methylation. Science 339, 222-226 (2013
121. Shiraki, N., et al. Methionine metabolism regulates maintenance and differentiation of human pluripotent stem cells. Cell Metab. 19, 780-794 (2014
122. 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
123. Lu, C., et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474-478 (2012
124. Saha, S. K., et al. Mutant IDH inhibits HNF 4α to block hepatocyte differentiation and promote biliary cancer. Nature 513, 110-114 (2014
125. Lu, C., et al. Induction of sarcomas by mutant IDH2. Genes Dev. 27, 1986-1998 (2013
126. Wang, F., et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622-626 (2013
127. Rohle, D., et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626-630 (2013
128. 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
129. 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
130. Flavahan, W. A., et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529, 110-114 (2016
131. Katainen, R., et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat. Genet. 47, 818-821 (2015
132. Ji, X., et al. 3D chromosome regulatory landscape of human pluripotent cells. Cell Stem Cell 18, 262-275 (2016
133. Hnisz, D., et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science 351, 1454-1458 (2016
134. 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
135. 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
136. Finley, L. W., et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 19, 416-428 (2011
137. Hirschey, M. D., et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121-125 (2010
138. 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
139. 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
140. Finley, L. W., et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS ONE 6, e23295 (2011
141. Cimen, H., et al. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry 49, 304-311 (2010
142. 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
143. 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
144. Lim, J. H., et al. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1α. Mol. Cell 38, 864-878 (2010
145. 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
146. 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
147. Lerin, C., et al. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC 1α. Cell Metab. 3, 429-438 (2006
148. 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
149. 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
150. Ventura, M., et al. Nuclear translocation of glyceraldehyde 3 phosphate dehydrogenase is regulated by acetylation. Int. J. Biochem. Cell Biol. 42, 1672-1680 (2010
151. 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
152. Vervoorts, J., et al. Stimulation of c MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep. 4, 484-490 (2003
153. 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
154. 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
155. 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
156. Masui, K., et al. Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance. Proc. Natl Acad. Sci. USA 112, 9406-9411 (2015
157. Shan, C., et al. Lysine acetylation activates 6 phosphogluconate dehydrogenase to promote tumor growth. Mol. Cell 55, 552-565 (2014
158. Patra, K. C., & Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 39, 347-354 (2014
159. Lin, R., et al. Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth. Mol. Cell 51, 506-518 (2014
160. 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
161. Kryukov, G. V., et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214-1218 (2016
162. Mavrakis, K. J., et al. Disordered methionine metabolism in MTAP/CDKN2A deleted cancers leads to dependence on PRMT5. Science 351, 1208-1213 (2016
163. Marjon, K., et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574-587 (2016
164. Hatzivassiliou, G., et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311-321 (2005
165. 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
166. Li, J. J., et al. 2 Hydroxy-N arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg. Med. Chem. Lett. 17, 3208-3211 (2007
167. 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
168. 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
169. 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
170. Madeo, F., Pietrocola, F., Eisenberg, T., & Kroemer, G. Caloric restriction mimetics: towards a molecular definition. Nat. Rev. Drug Discov. 13, 727-740 (2014
171. 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
172. Michelakis, E. D., et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl Med. 2, 31ra34 (2010
173. 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
174. 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
175. Shan, C., et al. Tyr 94 phosphorylation inhibits pyruvate dehydrogenase phosphatase 1 and promotes tumor growth. J. Biol. Chem. 289, 21413-21422 (2014
176. 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
177. Bantscheff, M., et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29, 255-265 (2011
178. West, A. C., & Johnstone, R. W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124, 30-39 (2014
179. Eckel-Mahan, K., & Sassone-Corsi, P. Metabolism and the circadian clock converge. Physiol. Rev. 93, 107-135 (2013
180. 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
181. 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
182. Cahill, G. F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1-22 (2006
183. Cederbaum, A. I. Alcohol metabolism. Clin. Liver Dis. 16, 667-685 (2012
184. Gao, X., et al. Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia. Nat. Commun. 7, 11960 (2016