肿瘤细胞中染色质修饰与代谢的相互调控

向莹; 熊洁; 李枫

doi:10.16689/j.cnki.cn11－9349/r.2019.04.021

PDF(760 KB)

肿瘤代谢与营养电子杂志 ›› 2019, Vol. 6 ›› Issue (4) : 499-504. DOI: 10.16689/j.cnki.cn11－9349/r.2019.04.021

综述

肿瘤细胞中染色质修饰与代谢的相互调控

向莹，熊洁，李枫

作者信息 +

Interplay between chromatin modifications and metabolism in cancer

XIANG Ying, XIONG Jie, LI Feng

Author information +

文章历史 +

摘要

肿瘤细胞中表观遗传的改变可影响癌基因和抑癌基因的表达水平；此外，肿瘤细胞中伴有的葡萄糖消耗增加、氧化磷酸化减少以及大量乳酸生成等代谢重编程现象，为生物合成提供了更多的中间代谢产物，并重新平衡了肿瘤细胞的氧化还原状态。而表观遗传的改变和代谢重编程均是肿瘤细胞的重要标志。随着研究的不断深入，发现肿瘤细胞代谢和表观遗传（主要是染色质修饰）之间存在着重要的双向调节机制。代谢重编程可影响染色质修饰酶所需的辅助因子，产生的肿瘤代谢产物作为染色质修饰酶的激动剂或拮抗剂，影响染色质修饰；反之，染色质修饰可以直接调控代谢酶的表达，或者改变参与细胞代谢控制的级联信号转导来调节细胞代谢。因此，代谢与表观遗传通过相互调控影响着细胞增殖、转移和多能性，并在肿瘤发生、发展中发挥关键作用。在这篇综述中，我们总结了肿瘤细胞中染色质修饰和代谢相关的最新发现及相互调控机制，以期揭示其在肿瘤发生、发展中的潜在作用，为发展基于肿瘤表观遗传修饰和代谢的靶向治疗方案提供新策略。

Abstract

The expression levels of oncogenes and tumor suppressor genes are altered significantly by epigenetic changes in cancer cells. In addition, tumor cells are associated with metabolic reprogramming events such as increased glucose consumption, decreased oxidative phosphorylation, and large amounts of lactic acid production, providing more intermediate metabolites for biosynthesis and rebalancing the redox state of tumor cells. Both epigenetic and metabolic changes are distinct hallmarks of cancer. Along with the research,it now become evident that there is an important bidirectional regulatory mechanism between cancer metabolism and epigenetics （mainly refer to chromatin modifications）. Metabolic reprogramming may affect the availability of cofactors required for normal function of epigenetic enzymes, and the oncometabolites probably act as agonists and/or antagonists of these enzymes, therefore affecting the epigenetic landscape. Moreover, chromatin modifications are able to directly regulate the expression of metabolic enzymes or change the signal transduction cascade involved in cell metabolism. Thus, epigenetic-metabolomic interplay plays a crucial role in tumorigenesis by sustaining cell proliferation, metastasis and pluripotency. Here, we summarized the mechanisms underlying mutual regulation of chromatin modifications and metabolism in cancer by reviewing the recent research progress, to explain their potential role in tumorigenesis, and provided new strategies for the development of therapies targeting epigenetic modifications and metabolism in cancer.

导出引用

向莹，熊洁，李枫. 肿瘤细胞中染色质修饰与代谢的相互调控[J]. 肿瘤代谢与营养电子杂志. 2019, 6(4): 499-504 https://doi.org/10.16689/j.cnki.cn11－9349/r.2019.04.021

XIANG Ying, XIONG Jie, LI Feng. Interplay between chromatin modifications and metabolism in cancer[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2019, 6(4): 499-504 https://doi.org/10.16689/j.cnki.cn11－9349/r.2019.04.021

参考文献

1.Warburg O. On respiratory impairment in cancer cells. Science. 1956；124（3215）:269-270.
2.Piunti A, Shilatifard A. Epigenetic balance of gene expression by Polycomb and COMPASS families. Science. 2016；352（6290）:aad9780.
3.Howard G, Eiges R, Gaudet F, et al. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene. 2008；27（3）:404-408.
4.Paredes J, Albergaria A, Oliveira JT, et al. P-cadherin overexpression is an indicator of clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter hypomethylation. Clin Cancer Res. 2005；11（16）:5869-5877.
5.Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994；91（21）:9700-9704.
6.Baylin SB. DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005；2 Suppl 1:S4-S11.
7.Ntziachristos P, Mullenders J, Trimarchi T, et al. Mechanisms of epigenetic regulation of leukemia onset and progression. Adv Immunol. 2013；117:1-38.
8.Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007；7（11）:823-833.
9.Yang Q, Zhu Q, Lu X, et al. G9a coordinates with the RPA complex to promote DNA damage repair and cell survival. Proc Natl Acad Sci U S A. 2017；114（30）:E6054-E6063.
10.Park SJ, Kim JG, Son TG, et al. The histone demethylase JMJD1A regulates adrenomedullin-mediated cell proliferation in hepatocellular carcinoma under hypoxia. Biochem Biophys Res Commun. 2013；434（4）:722-727.
11.Faubert B, Li KY, Cai L, et al. Lactate metabolism in human lung tumors. Cell. 2017；171（2）:358-371.
12.Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the TCA cycle via circulating lactate. Nature. 2017；551（7678）:115-118.
13.Jin L, Li D, Alesi GN, et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell. 2015；27（2）:257-270.
14.Santos CR, Schulze A. Lipid metabolism in cancer. FEBS J. 2012；279（15）:2610-2623.
15.Abramson HN. The lipogenesis pathway as a cancer target. J Med Chem. 2011；54（16）:5615-5638.
16.Reid MA, Dai Z, Locasale JW. The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat Cell Biol. 2017；19（11）:1298-1306.
17.Sharma U, Rando OJ. Metabolic Inputs into the Epigenome. Cell Metab. 2017；25（3）:544-558.
18.Wong CC, Qian Y, Yu J. Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches. Oncogene. 2017；36（24）:3359-3374.
19.Desai S, Ding M, Wang B, et al. Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers. Oncotarget. 2014；5（18）:8202-8210.
20.Kim HS, Xiao C, Wang RH, et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 2010；12（3）:224-236.
21.Shimazu T, Hirschey MD, Hua L, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010；12（6）:654-661.
22.Wang L, Xu S, Lee JE, et al. Histone H3K9 methyltransferase G9a represses PPARgamma expression and adipogenesis. EMBO J. 2013；32（1）:45-59.
23.Tateishi K, Okada Y, Kallin EM, et al. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature. 2009；458（7239）:757-761.
24.Mentch SJ, Mehrmohamadi M, Huang L, et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 2015；22（5）:861-873.
25.Martinez-Chantar ML, Vazquez-Chantada M, Ariz U, et al. Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology. 2008；47（4）:1191-1199.
26.Xiao M, Yang H, Xu W, 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（12）:1326-1338.
27.Rabhi N, Hannou SA, Froguel P, et al. Cofactors as metabolic sensors driving cell adaptation in physiology and disease. Front Endocrinol （Lausanne）. 2017；8:304.
28.Kim JA, Yeom YI. Metabolic signaling to epigenetic alterations in cancer. Biomol Ther （Seoul）. 2018；26（1）:69-80.
29.Hwang IY, Kwak S, Lee S, et al. Psat1-dependent fluctuations in alpha-ketoglutarate affect the timing of esc differentiation. Cell Metab. 2016；24（3）:494-501.
30.TeSlaa T, Chaikovsky AC, Lipchina I, et al. alpha-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 2016；24（3）:485-493.
31.Pan M, Reid MA, Lowman XH, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016；18（10）:1090-1101.
32.Shi L, Tu BP. Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol. 2015；33:125-131.
33.Wellen KE, Hatzivassiliou G, Sachdeva UM, et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009；324（5930）:1076-1080.
34.Migita T, Narita T, Nomura K, et al. ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res. 2008；68（20）:8547-8554.
35.Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014；6（4）:a018713.
36.Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, et al. Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells. Cell Cycle. 2012；11（21）:3956-3963.
37.Wagner W, Ciszewski WM, Kania KD. L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation. Cell Commun Signal. 2015；13:36.
38.Moiseeva O, Bourdeau V, Roux A, et al. Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol Cell Biol. 2009；29（16）:4495-4507.
39.Baracca A, Chiaradonna F, Sgarbi G, et al. Mitochondrial Complex I decrease is responsible for bioenergetic dysfunction in K-ras transformed cells. Biochim Biophys Acta. 2010；1797（2）:314-323.
40.Ricoult SJ, Yecies JL, Ben-Sahra I, et al. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene. 2016；35（10）:1250-1260.
41.Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004；64（7）:2627-2633.
42.Bensaad K, Tsuruta A, Selak MA, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006；126（1）:107-120.
43.Matoba S, Kang JG, Patino WD, et al. p53 regulates mitochondrial respiration. Science. 2006；312（5780）:1650-1653.
44.Jiang P, Du W, Wang X, et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 2011；13（3）:310-316.
45.Kroemer G, Pouyssegur J. Tumor cell metabolism: cancers Achilles heel. Cancer Cell. 2008；13（6）:472-482.
46.Dang L, White DW, Gross S, et al. Cancer-associated IDH1mutations produce 2-hydroxyglutarate. Nature. 2009；462（7274）:739-744.
47.Rzem R, Veiga-da-Cunha M, Noel G, et al. A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. Proc Natl Acad Sci U S A. 2004；101（48）:16849-16854.
48.Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011；19（1）:17-30.
49.Sasaki M, Knobbe CB, Munger JC, et al. IDH1（R132H） mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012；488（7413）:656-659.
50.Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012；483（7390）:474-478.
51.Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer Metab. 2014；2:10.
52.Bardella C, Pollard PJ, Tomlinson I. SDH mutations in cancer. Biochim Biophys Acta. 2011；1807（11）:1432-1443.
53.Letouze E, Martinelli C, Loriot C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013；23（6）:739-752.