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J Zhejiang Univ (Med Sci)  2021, Vol. 50 Issue (1): 1-16    DOI: 10.3724/zdxbyxb-2021-0053
    
Research advances on epigenetics and cancer metabolism
HAN Hengyi(),FENG Fan,LI Haitao()
School of Medicine,Tsinghua University,Beijing 100084,China
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Abstract  

Epigenetics concerns gene regulatory mechanisms beyond DNA sequence,such as DNA methylation,histone modification,chromatin remodeling,and non-coding RNA. Epigenetic mechanisms play a key role in development,cell fate decision and tumorigenesis. Chromatin modifications and its high order structure across our genome are major forms of epigenetic information,and its establishment and maintenance are closely related to cell metabolism. Metabolic changes in cancer cells include aerobic glycolysis,increased glucose uptake,abnormally active glutamine metabolism,and the use of non-conventional energy supply. These changes meet the vigorous energy and matter needs for the development and spread of cancer,and help tumor cells adapt to hypoxia microenvironment for their survival,proliferation,invasion and migration. There is a complex relationship between epigenetic modifications and cell metabolism in tumor. On the one hand,metabolites in tumor cells may act as cofactors,modification donors or antagonists of epigenetic enzymes,thus modulating the epigenetic landscape. On the other hand,epigenetic modifications can directly regulate the expression of metabolic enzymes,transporters,signaling pathway and transcription factors to affect cell metabolism. This article reviews the crosstalk between epigenetics and cancer metabolism,to explore their potential future applications in the treatment of tumors.



Key wordsEpigenetics      Metabolism      Tumor      DNA methylation      Histone modification      Non-coding RNA      Epigenetic landscape      Review     
Received: 12 January 2021      Published: 14 May 2021
CLC:  R730.23  
  R730.23  
  A  
Corresponding Authors: LI Haitao     E-mail: hanhy17@mails.tsinghua.edu.cn;lht@tsinghua.edu.cn
Cite this article:

HAN Hengyi,FENG Fan,LI Haitao. Research advances on epigenetics and cancer metabolism. J Zhejiang Univ (Med Sci), 2021, 50(1): 1-16.

URL:

http://www.zjujournals.com/med/10.3724/zdxbyxb-2021-0053     OR     http://www.zjujournals.com/med/Y2021/V50/I1/1


表观遗传与肿瘤代谢研究进展

表观遗传学主要关注DNA甲基化、组蛋白修饰、染色质重塑,以及非编码RNA等超越DNA序列的基因调控机制。表观遗传机制参与了个体发育、细胞命运决定和肿瘤发生等众多生物学过程。其中表观遗传信息以各种染色质修饰和高级结构的形式存储于基因组中,它的建立和维持与细胞代谢紧密相关。肿瘤细胞中存在的代谢改变包括有氧糖酵解、葡萄糖摄取量增加、谷氨酰胺代谢异常活跃、利用非主要供能物质供能等,这些改变满足了肿瘤发生发展过程中旺盛的能量和物质需求,帮助细胞适应缺氧的肿瘤微环境,进而为肿瘤增殖、侵袭、迁移等生物活动提供支持。肿瘤细胞的表观遗传修饰与代谢之间存在复杂的相互关系,一方面肿瘤细胞中的代谢产物作为表观修饰酶的辅因子、修饰供体或拮抗分子影响表观修饰景观;另一方面表观遗传修饰可以直接改变代谢酶和转运蛋白的表达或通过影响信号转导和转录因子的表达调控细胞代谢。本文综述了不同表观遗传学过程与肿瘤细胞代谢之间的相互作用,并展望两者在肿瘤治疗中的潜在应用前景。


关键词: 表观遗传学,  代谢,  肿瘤,  DNA甲基化,  组蛋白修饰,  非编码RNA,  表观景观,  综述 
[1]   WARBURG O, WIND F, NEGELEIN E . The metabo-lismof tumors in the body[J]. J General Physiol, 1927, 8(6): 519-530.
doi: 10.1085/jgp.8.6.519
[2]   DEBERARDINIS R J, MANCUSO A, DAIKHIN E, et al. Beyond aerobic glycolysis:transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis[J]. Proc Natl Acad Sci USA, 2007, 104(49): 19345-19350.
doi: 10.1073/pnas.0709747104
[3]   HSU P P, SABATINI D M . Cancer cell metabolism:warburg and beyond[J]. Cell, 2008, 134(5): 703-707.
doi: 10.1016/j.cell.2008.08.021
[4]   JAENISCH R, BIRD A . Epigenetic regulation of gene expression:how the genome integrates intrinsic and environmental signals[J]. Nat Genet, 2003, 33(S3): 245-254.
doi: 10.1038/ng1089
[5]   HERCEG Z, VAISSIèRE T . Epigenetic mechanisms and cancer:an interface between the environment and the genome[J]. Epigenetics, 2011, 6(7): 804-819.
doi: 10.4161/epi.6.7.16262
[6]   EDEN A, GAUDET F, WAGHMARE A, et al. Chromosomal instability and tumors promoted by DNA hypomethylation[J]. Science, 2003, 300(5618): 455.
doi: 10.1126/science.1083557
[7]   FRAGA M F, BALLESTAR E, VILLAR-GAREA A, et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer[J]. Nat Genet, 2005, 37(4): 391-400.
doi: 10.1038/ng1531
[8]   MENTCH S J, MEHRMOHAMADI M, HUANG L, et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism[J]. Cell Metab, 2015, 22(5): 861-873.
doi: 10.1016/j.cmet.2015.08.024
[9]   LEE J V, CARRER A, SHAH S, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation[J]. Cell Metab, 2014, 20(2): 306-319.
doi: 10.1016/j.cmet.2014.06.004
[10]   LI X, KAZGAN N . Mammalian sirtuins and energy metabolism[J]. Int J Biol Sci, 2011, 7(5): 575-587.
doi: 10.7150/ijbs.7.575
[11]   BIRD A P . CPG-rich islands and the function of dna methylation[J]. Nature, 1986, 321(6067): 209-213.
doi: 10.1038/321209a0
[12]   YEIVIN A,RAZIN A. Gene methylation patterns and expression[J]. Exs,1993,64:523–568.DOI:10. 1007/978-3-0348-9118-9_24 .
[13]   ROBERTSON K D, UZVOLGYI E, LIANG G, et al. The human DNA methyltransferases (DNMTs) 1,3a and 3b:coordinate mRNA expression in normal tissues and overexpression in tumors[J]. Nucleic Acids Res, 1999, 27(11): 2291-2298.
doi: 10.1093/nar/27.11.2291
[14]   HAASE C, BERGMANN R, FUECHTNER F, et al. L-type amino acid transporters LAT1 and LAT4 in cancer:uptake of 3-O-Methyl-6-18F-Fluoro-L-Dopa in human adenocarcinoma and squamous cell carcinoma in vitro and in vivo[J] . J Nucl Med, 2007, 48(12): 2063-2071.
doi: 10.2967/jnumed.107.043620
[15]   MARTíNEZ-CHANTAR M L, VáZQUEZ-CHANTADA M, ARIZ U, et al. Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice[J]. Hepatology, 2007, 47(4): 1191-1199.
doi: 10.1002/hep.22159
[16]   GUO J U, SU Y, ZHONG C, et al. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain[J]. Cell, 2011, 145(3): 423-434.
doi: 10.1016/j.cell.2011.03.022
[17]   KOHLI R M, ZHANG Y . TET enzymes,TDG and the dynamics of DNA demethylation[J]. Nature, 2013, 502(7472): 472-479.
doi: 10.1038/nature12750
[18]   GAMBICHLER T, SAND M, SKRYGAN M . Loss of 5-hydroxymethylcytosine and ten-eleven translocation 2 protein expression in malignant melanoma[J]. Melanoma Res, 2013, 23(3): 218-220.
doi: 10.1097/CMR.0b013e32835f9bd4
[19]   KUDO Y, TATEISHI K, YAMAMOTO K, et al. Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation[J]. Cancer Sci, 2012, 103(4): 670-676.
doi: 10.1111/j.1349-7006.2012.02213.x
[20]   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[J]. Genes Dev, 2012, 26(12): 1326-1338.
doi: 10.1101/gad.191056.112
[21]   IKEGAMI K, OHGANE J, TANAKA S, et al. Interplay between DNA methylation,histone modification and chromatin remodeling in stem cells and during development[J]. Int J Dev Biol, 2009, 53(2-3): 203-214.
doi: 10.1387/ijdb.082741ki
[22]   DESAI S, DING M, WANG B, et al. Tissue-specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers[J]. Oncotarget, 2014, 5(18): 8202-8210.
doi: 10.18632/oncotarget.1159
[23]   NING X, QI H, LI R, et al. Synthesis and antitumor activity of novel 2,3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform[J]. J Enzyme Inhib Med Chem, 2018, 33(1): 126-129.
doi: 10.1080/14756366.2017.1404591
[24]   KANEKO Y,SHIBUYA M,NAKAYAMA T,et al. Hypomethylation of C-MYC and epidermal growth-factor receptor genes in human hepatocellular-carcinoma and fetal liver[J]. Jap J Cancer Res,1985,76(12):1136–1140 .
[25]   HANADA M,DELIA D,AIELLO A,et al. BCL-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic-leukemia[J]. Blood,1993,82(6):1820–1828 .
[26]   POGELL B M,MCGILVERY R W. Partial purification of fructose-1,6-diphosphatase[J]. J Biol Chem,1954,208(1):149–157 .
[27]   DONG C, YUAN T, WU Y, et al. Loss of FBP1 by snail-mediated repression provides metabolic advantages in basal-like breast cancer[J]. Cancer Cell, 2013, 23(3): 316-331.
doi: 10.1016/j.ccr.2013.01.022
[28]   ZHANG J, WANG J, XING H, et al. Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells[J]. Mol Cell Biochem, 2016, 411(1-2): 331-340.
doi: 10.1007/s11010-015-2595-8
[29]   BáRCENA-VARELA M, CARUSO S, LLERENA S, et al. Dual targeting of histone methyltransferase G9a and DNA‐methyltransferase 1 for the treatment of experimental hepatocellular carcinoma[J]. Hepatology, 2019, 69(2): 587-603.
doi: 10.1002/hep.30168
[30]   LOPEZ-SERRA P,MARCILLA M,VILLANUEVA A,et al. A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect [J]. Nat Commun,2014,5:3608.DOI:10.1038/ncomms4608 .
[31]   DüVEL K, YECIES J L, MENON S, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1[J]. Mol Cell, 2010, 39(2): 171-183.
doi: 10.1016/j.molcel.2010.06.022
[32]   SEMENZA G L . Regulation of cancer cell metabolism by hypoxia-inducible factor 1[J]. Semin Cancer Biol, 2009, 19(1): 12-16.
doi: 10.1016/j.semcancer.2008.11.009
[33]   KANG Y H, LEE H S, KIM W H . Promoter methylation and silencing of PTEN in gastric carcinoma[J]. Lab Invest, 2002, 82(3): 285-291.
doi: 10.1038/labinvest.3780422
[34]   VANHARANTA S, SHU W, BRENET F, et al. Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer[J]. Nat Med, 2013, 19(1): 50-56.
doi: 10.1038/nm.3029
[35]   RAWLUSZKO A A, BUJNICKA K E, HORBACKA K, et al. Expression and DNA methylation levels of prolyl hydroxylases PHD1,PHD2,PHD3 and asparaginyl hydroxylase FIH in colorectal cancer[J]. BMC Cancer, 2013, 13(1): 526.
doi: 10.1186/1471-2407-13-526
[36]   TROJAN J, BRIEGER A, RAEDLE J, et al. 5’-CpG island methylation of the LKB1/STK11 promoter and allelic loss at chromosome 19p13.3 in sporadic colorectal cancer[J]. Gut, 2000, 47(2): 272-276.
doi: 10.1136/gut.47.2.272
[37]   XU Y, LIU C, CHEN S, et al. Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson’s disease[J] . Cell Signal, 2014, 26(8): 1680-1689.
doi: 10.1016/j.cellsig.2014.04.009
[38]   LI H,WANG J,XU H,et al. Decreased fructose-1,6-bisphosphatase-2 expression promotes glycolysis and growth in gastric cancer cells [J]. Mol Cancer,2013,12(1):110.DOI:10.1186/1476-4598-12-110 .
[39]   KOUZARIDES T . Chromatin modifications and their function[J]. Cell, 2007, 128(4): 693-705.
doi: 10.1016/j.cell.2007.02.005
[40]   STRAHL B D, ALLIS C D . The language of covalent histone modifications[J]. Nature, 2000, 403(6765): 41-45.
doi: 10.1038/47412
[41]   JENUWEIN T, ALLIS C D . Translating the histone code[J]. Science, 2001, 293(5532): 1074-1080.
doi: 10.1126/science.1063127
[42]   ZHANG Y, REINBERG D . Transcription regulation by histone methylation:interplay between different covalent modifications of the core histone tails[J]. Genes Dev, 2001, 15(18): 2343-2360.
doi: 10.1101/gad.927301
[43]   MARTIN C, ZHANG Y . The diverse functions of histone lysine methylation[J]. Nat Rev Mol Cell Biol, 2005, 6(11): 838-849.
doi: 10.1038/nrm1761
[44]   SHILATIFARD A . Chromatin modifications by methylation and ubiquitination:implications in the regulation of gene expression[J]. Annu Rev Biochem, 2006, 75(1): 243-269.
doi: 10.1146/annurev.biochem.75.103004.142422
[45]   DORRANCE A M, LIU S, YUAN W, et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations[J] . J Clin Invest, 2006, 116(10): 2707-2716.
doi: 10.1172/jci25546
[46]   SIMON J A, LANGE C A . Roles of the EZH2 histone methyltransferase in cancer epigenetics[J]. Mutat Res/Fundamental Mol Mech Mutagenesis, 2008, 647(1-2): 21-29.
doi: 10.1016/j.mrfmmm.2008.07.010
[47]   MCCABE M T, OTT H M, GANJI G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations[J]. Nature, 2012, 492(7427): 108-112.
doi: 10.1038/nature11606
[48]   VARAMBALLY S, DHANASEKARAN S M, ZHOU M, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer[J]. Nature, 2002, 419(6907): 624-629.
doi: 10.1038/nature01075
[49]   HU H, QIAN K, HO M C, et al. Small molecule inhibitors of protein arginine methyltransferases[J]. Expert Opin Investig Drugs, 2016, 25(3): 335-358.
doi: 10.1517/13543784.2016.1144747
[50]   MATHIOUDAKI K, SCORILAS A, ARDAVANIS A, et al. Clinical evaluation of PRMT1 gene expression in breast cancer[J]. Tumor Biol, 2011, 32(3): 575-582.
doi: 10.1007/s13277-010-0153-2
[51]   CHEUNG N, FUNG T K, ZEISIG B B, et al. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia[J]. Cancer Cell, 2016, 29(1): 32-48.
doi: 10.1016/j.ccell.2015.12.007
[52]   KOOISTRA S M, HELIN K . Molecular mechanisms and potential functions of histone demethylases[J]. Nat Rev Mol Cell Biol, 2012, 13(5): 297-311.
doi: 10.1038/nrm3327
[53]   FENG Z, YAO Y, ZHOU C, et al. Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia[J]. J Hematol Oncol, 2016, 9(1): 24.
doi: 10.1186/s13045-016-0252-7
[54]   VERDIN E, OTT M . 50 years of protein acetylation:from gene regulation to epigenetics,metabolism and beyond[J]. Nat Rev Mol Cell Biol, 2015, 16(4): 258-264.
doi: 10.1038/nrm3931
[55]   KOUZARIDES T . Histone acetylases and deacetylases in cell proliferation[J]. Curr Opin Genets Dev, 1999, 9(1): 40-48.
doi: 10.1016/s0959-437x(99)80006-9
[56]   WELLEN K E, HATZIVASSILIOU G, SACHDEVA U M, et al. ATP-citrate lyase links cellular metabolism to histone acetylation[J]. Science, 2009, 324(5930): 1076-1080.
doi: 10.1126/science.1164097
[57]   KNOEPFLER P S, ZHANG X, CHENG P F, et al. Myc influences global chromatin structure[J]. EMBO J, 2006, 25(12): 2723-2734.
doi: 10.1038/sj.emboj.7601152
[58]   RICHTERS A, KOEHLER A N . Epigenetic modula- tion using small molecules - targeting histone acetyltransferases in disease[J]. Curr Med Chem, 2017, 24(37): 4121-4150.
doi: 10.2174/0929867324666170223153115
[59]   SPANGE S, WAGNER T, HEINZEL T, et al. Acetylation of non-histone proteins modulates cellular signalling at multiple levels[J]. Int J Biochem Cell Biol, 2009, 41(1): 185-198.
doi: 10.1016/j.biocel.2008.08.027
[60]   SEGRé C V, CHIOCCA S . Regulating the regulators:the post-translational code of class I HDAC1 and HDAC2[J]. J Biomed Biotech, 2011, 690848.
doi: 10.1155/2011/690848
[61]   ZHANG Z G, QIN C Y . Sirt6 suppresses hepatocellular carcinoma cell growth via inhibiting the extracellular signal-regulated kinase signaling pathway[J]. Mol Med Rep, 2014, 9(3): 882-888.
doi: 10.3892/mmr.2013.1879
[62]   BARBER M F, MICHISHITA-KIOI E, XI Y, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation[J]. Nature, 2012, 487(7405): 114-118.
doi: 10.1038/nature11043
[63]   LIU P Y, XU N, MALYUKOVA A, et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins[J]. Cell Death Differ, 2013, 20(3): 503-514.
doi: 10.1038/cdd.2012.147
[64]   CHEN Y, SPRUNG R, TANG Y, et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones[J]. Mol Cellular Proteomics, 2007, 6(5): 812-819.
doi: 10.1074/mcp.M700021-MCP200
[65]   TAN M, LUO H, LEE S, et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification[J]. Cell, 2011, 146(6): 1016-1028.
doi: 10.1016/j.cell.2011.08.008
[66]   XIE Z, DAI J, DAI L, et al. Lysine succinylation and lysine malonylation in histones[J]. Mol Cellular Proteomics, 2012, 11(5): 100-107.
doi: 10.1074/mcp.M111.015875
[67]   XIE Z, ZHANG D, CHUNG D, et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation[J]. Mol Cell, 2016, 62(2): 194-206.
doi: 10.1016/j.molcel.2016.03.036
[68]   LEE K K, WORKMAN J L . Histone acetyltransferase complexes:one size doesn’t fit all[J]. Nat Rev Mol Cell Biol, 2007, 8(4): 284-295.
doi: 10.1038/nrm2145
[69]   ROTH S Y, DENU J M, ALLIS C D . Histone acetyltransferases[J]. Annu Rev Biochem, 2001, 70(1): 81-120.
doi: 10.1146/annurev.biochem.70.1.81
[70]   CHENG Z, TANG Y, CHEN Y, et al. Molecular characterization of propionyllysines in non-histone proteins[J]. Mol Cell Proteomics, 2009, 8(1): 45-52.
doi: 10.1074/mcp.M800224-MCP200
[71]   KACZMARSKA Z, ORTEGA E, GOUDARZI A, et al. Structure of p300 in complex with acyl-CoA variants[J]. Nat Chem Biol, 2017, 13(1): 21-29.
doi: 10.1038/nchembio.2217
[72]   SABARI B R, TANG Z, HUANG H, et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation[J]. Mol Cell, 2015, 58(2): 203-215.
doi: 10.1016/j.molcel.2015.02.029
[73]   BERNDSEN C E, ALBAUGH B N, TAN S, et al. Catalytic mechanism of a MYST family histone acetyltransferase[J]. Biochemistry, 2007, 46(3): 623-629.
doi: 10.1021/bi602513x
[74]   LEEMHUIS H, PACKMAN L C, NIGHTINGALE K P, et al. The human histone acetyltransferase P/CAF is a promiscuous histone propionyltransferase[J]. Chembiochem, 2008, 9(4): 499-503.
doi: 10.1002/cbic.200700556
[75]   RINGEL A E, WOLBERGER C . Structural basis for acyl-group discrimination by human Gcn5L2[J]. Acta Crystlogr D Struct Biol, 2016, 72(7): 841-848.
doi: 10.1107/s2059798316007907
[76]   PENG C, LU Z, XIE Z, et al. The first identification oflysine malonylation substrates and its regulatory enzyme[J]. Mol Cell Proteomics, 2011, 10(12): M111.012658.
doi: 10.1074/mcp.M111.012658
[77]   JIANG G, NGUYEN D, ARCHIN N M, et al. HIV latency is reversed by ACSS2-driven histone crotonylation[J]. J Clin Invest, 2018, 128(3): 1190-1198.
doi: 10.1172/jci98071
[78]   MASHIMO T, PICHUMANI K, VEMIREDDY V, et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases[J]. Cell, 2014, 159(7): 1603-1614.
doi: 10.1016/j.cell.2014.11.025
[79]   COMERFORD S A, HUANG Z, DU X, et al. Acetate dependence of tumors[J]. Cell, 2014, 159(7): 1591-1602.
doi: 10.1016/j.cell.2014.11.020
[80]   HALLOWS W C, LEE S, DENU J M . Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases[J]. Proc Natl Acad Sci USA, 2006, 103(27): 10230-10235.
doi: 10.1073/pnas.0604392103
[81]   FELDMAN J L, BAEZA J, DENU J M . Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins[J]. J Biol Chem, 2013, 288(43): 31350-31356.
doi: 10.1074/jbc.C113.511261
[82]   TAN M, PENG C, ANDERSON K A, et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5[J]. Cell Metab, 2014, 19(4): 605-617.
doi: 10.1016/j.cmet.2014.03.014
[83]   PARK J, CHEN Y, TISHKOFF D X, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways[J]. Mol Cell, 2013, 50(6): 919-930.
doi: 10.1016/j.molcel.2013.06.001
[84]   DU J, ZHOU Y, SU X, et al. Sirt5 is a NAD-dependentprotein lysine demalonylase and desuccinylase[J]. Science, 2011, 334(6057): 806-809.
doi: 10.1126/science.1207861
[85]   ALAMOUDI A A, ALNOURY A, GAD H . miRNA in tumour metabolism and why could it be the preferred pathway for energy reprograming[J]. Brief Funct Genomics, 2018, 17(3): 157-169.
doi: 10.1093/bfgp/elx023
[86]   COHEN A L, HOLMEN S L, COLMAN H . IDH1 and IDH2 mutations in gliomas[J]. Curr Neurol NeuroSci Rep, 2013, 13(5): 345.
doi: 10.1007/s11910-013-0345-4
[87]   FIGLIA G, WILLNOW P, TELEMAN A A . Metabo- lites regulate cell signaling and growth via covalent modification of proteins[J]. Dev Cell, 2020, 54(2): 156-170.
doi: 10.1016/j.devcel.2020.06.036
[88]   HAN X, XIANG X, YANG H, et al. p300-catalyzed lysine crotonylation promotes the proliferation,invasion,and migration of HeLa cells via heterogeneous nuclear ribonucleoprotein A1[J]. Anal Cellular Pathol, 2020, 1-6.
doi: 10.1155/2020/5632342
[89]   HUANG H, WANG D L, ZHAO Y . Quantitative crotonylome analysis expands the roles of p300 in the regulation of lysine crotonylation pathway[J]. Proteomics, 2018, 18(15): 1700230.
doi: 10.1002/pmic.201700230
[90]   LIU J, YUE Y, HAN D, et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N 6-adenosine methylation[J] . Nat Chem Biol, 2014, 10(2): 93-95.
doi: 10.1038/nchembio.1432
[91]   PING X L, SUN B F, WANG L, et al. Mammalian WTAP is a regulatory subunit of the RNA N 6-methyladenosine methyltransferase[J] . Cell Res, 2014, 24(2): 177-189.
doi: 10.1038/cr.2014.3
[92]   JIA G, FU Y, ZHAO X, et al. N 6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO[J] . Nat Chem Biol, 2011, 7(12): 885-887.
doi: 10.1038/nchembio.687
[93]   ZHENG G, DAHL J A, NIU Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J]. Mol Cell, 2013, 49(1): 18-29.
doi: 10.1016/j.molcel.2012.10.015
[94]   DOMINISSINI D, MOSHITCH-MOSHKOVITZ S, SCHWARTZ S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J]. Nature, 2012, 485(7397): 201-206.
doi: 10.1038/nature11112
[95]   WANG X, LU Z, GOMEZ A, et al. N 6-methyladeno- sine-dependent regulation of messenger RNA stability[J] . Nature, 2014, 505(7481): 117-120.
doi: 10.1038/nature12730
[96]   WANG X, ZHAO B S, ROUNDTREE I A, et al. N 6-methyladenosine modulates messenger RNA translation efficiency[J] . Cell, 2015, 161(6): 1388-1399.
doi: 10.1016/j.cell.2015.05.014
[97]   XIAO W, ADHIKARI S, DAHAL U, et al. Nuclear m 6 a reader YTHDC1 regulates mRNA splicing[J] . Mol Cell, 2016, 61(4): 507-519.
doi: 10.1016/j.molcel.2016.01.012
[98]   LI Z, WENG H, SU R, et al. FTO plays an oncogenicrole in acute myeloid leukemia as a N 6-methyladenosine RNA demethylase[J] . Cancer Cell, 2017, 31(1): 127-141.
doi: 10.1016/j.ccell.2016.11.017
[99]   ZHANG S, ZHAO B S, ZHOU A, et al. M 6 a demethylase alkbh5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program[J] . Cancer Cell, 2017, 31(4): 591-606.e6.
doi: 10.1016/j.ccell.2017.02.013
[100]   TANABE A, TANIKAWA K, TSUNETOMI M, et al. RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1α mRNA is translated[J]. Cancer Lett, 2016, 376(1): 34-42.
doi: 10.1016/j.canlet.2016.02.022
[101]   SU R, DONG L, LI C, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling[J]. Cell, 2018, 172(1-2): 90-105.e23.
doi: 10.1016/j.cell.2017.11.031
[102]   CUI Q, SHI H, YE P, et al. m 6 a RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells[J] . Cell Rep, 2017, 18(11): 2622-2634.
doi: 10.1016/j.celrep.2017.02.059
[103]   LIU J, ECKERT M A, HARADA B T, et al. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer[J]. Nat Cell Biol, 2018, 20(9): 1074-1083.
doi: 10.1038/s41556-018-0174-4
[104]   ALARCóN C R, LEE H, GOODARZI H, et al. N 6-methyladenosine marks primary microRNAs for processing[J] . Nature, 2015, 519(7544): 482-485.
doi: 10.1038/nature14281
[105]   ZHOU C, MOLINIE B, DANESHVAR K, et al. Genome-wide maps of m6a circrnas identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs[J]. Cell Rep, 2017, 20(9): 2262-2276.
doi: 10.1016/j.celrep.2017.08.027
[106]   ZHOU K I, PARISIEN M, DAI Q, et al. N 6-methyladenosine modification in a long noncoding rna hairpin predisposes its conformation to protein binding[J] . J Mol Biol, 2016, 428(5): 822-833.
doi: 10.1016/j.jmb.2015.08.021
[107]   WEI J W, HUANG K, YANG C, et al. Non-coding RNAs as regulators in epigenetics[J]. Oncology Rep, 2017, 37(1): 3-9.
doi: 10.3892/or.2016.5236
[108]   BARTEL D P . MicroRNAs:target recognition and regulatory functions[J]. Cell, 2009, 136(2): 215-233.
doi: 10.1016/j.cell.2009.01.002
[109]   MACHEDA M L, ROGERS S, BEST J D . Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer[J]. J Cell Physiol, 2005, 202(3): 654-662.
doi: 10.1002/jcp.20166
[110]   CHEN B, TANG H, LIU X, et al. miR-22 as a prognostic factor targets glucose transporter protein type 1 in breast cancer[J]. Cancer Lett, 2015, 356(2): 410-417.
doi: 10.1016/j.canlet.2014.09.028
[111]   YAMASAKI T, SEKI N, YOSHINO H, et al. Tumor-suppressive microRNA-1291 directly regulates glucose transporter 1 in renal cell carcinoma[J]. Cancer Sci, 2013, 104(11): 1411-1419.
doi: 10.1111/cas.12240
[112]   FEI X, QI M, WU B, et al. MicroRNA-195-5p suppresses glucose uptake and proliferation of human bladder cancer T24 cells by regulating GLUT3 expression[J] . FEBS Lett, 2012, 586(4): 392-397.
doi: 10.1016/j.febslet.2012.01.006
[113]   GREGERSEN L H, JACOBSEN A, FRANKEL L B, et al. MicroRNA-143 down-regulates hexokinase 2 in colon cancer cells[J]. BMC Cancer, 2012, 12(1): 232.
doi: 10.1186/1471-2407-12-232
[114]   SONG J, WU X, LIU F, et al. Long non-coding RNAPVT1 promotes glycolysis and tumor progression by regulating miR-497/HK2 axis in osteosarcoma[J]. Biochem BioPhys Res Commun, 2017, 490(2): 217-224.
doi: 10.1016/j.bbrc.2017.06.024
[115]   TSAI W C, HSU P W C, LAI T C, et al. MicroRNA-122,a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma[J]. Hepatology, 2009, 49(5): 1571-1582.
doi: 10.1002/hep.22806
[116]   LI Y, KONG D, AHMAD A, et al. Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion[J]. Epigenetics, 2012, 7(8): 940-949.
doi: 10.4161/epi.21236
[117]   KEFAS B, COMEAU L, ERDLE N, et al. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells[J]. Neuro-Oncology, 2010, 12(11): 1102-1112.
doi: 10.1093/neuonc/noq080
[118]   LIU A M, XU Z, SHEK F H, et al. miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma[J/OL]. PLoS One, 2014, 9(1): e86872.
doi: 10.1371/journal.pone.0086872
[119]   TANIGUCHI K, SUGITO N, KUMAZAKI M, et al. MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer[J]. Cancer Lett, 2015, 363(1): 17-27.
doi: 10.1016/j.canlet.2015.03.026
[120]   WANG J, WANG H, LIU A, et al. Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer[J]. Oncotarget, 2015, 6(23): 19456-19468.
doi: 10.18632/oncotarget.3318
[121]   LIU L, WANG Y, BAI R, et al. MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1α regulation[J/OL]. Oncogenesis, 2016, 5(5): e224.
doi: 10.1038/oncsis.2016.35
[122]   TAKAHASHI K, YAN I K, HAGA H, et al. Modulation of hypoxia-signaling pathways by extracellular linc-RoR[J]. J Cell Sci, 2014, 127(7): 1585-1594.
doi: 10.1242/jcs.141069
[123]   CHEN Z, ZENG H, GUO Y, et al. miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc[J]. J Exp Clin Cancer Res, 2010, 29(1): 151.
doi: 10.1186/1756-9966-29-151
[124]   YAMAMURA S, SAINI S, MAJID S, et al. MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells[J/OL]. PLoS One, 2012, 7(1): e29722.
doi: 10.1371/journal.pone.0029722
[125]   TSAI W C, HSU S D, HSU C S, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis[J]. J Clin Invest, 2012, 122(8): 2884-2897.
doi: 10.1172/jci63455
[126]   HE J, ZHAO K, ZHENG L, et al. Upregulation of microRNA-122 by farnesoid X receptor suppresses the growth of hepatocellular carcinoma cells[J]. Mol Cancer, 2015, 14(1): 163.
doi: 10.1186/s12943-015-0427-9
[127]   ESAU C, DAVIS S, MURRAY S F, et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting[J]. Cell Metab, 2006, 3(2): 87-98.
doi: 10.1016/j.cmet.2006.01.005
[128]   CUI M, WANG Y, SUN B, et al. MiR-205 modulatesabnormal lipid metabolism of hepatoma cells via targeting acyl-CoA synthetase long-chain family member 1 (ACSL1) mRNA[J]. Biochem BioPhys Res Commun, 2014, 444(2): 270-275.
doi: 10.1016/j.bbrc.2014.01.051
[129]   NOGUCHI S, IWASAKI J, KUMAZAKI M, et al. Chemically modified synthetic microRNA-205 inhibits the growth of melanoma cells in vitro and in vivo[J] . Mol Ther, 2013, 21(6): 1204-1211.
doi: 10.1038/mt.2013.70
[130]   PHANG J M, LIU W, HANCOCK C N, et al. Proline metabolism and cancer[J]. Curr Opin Clin Nutrition Metabolic Care, 2015, 18(1): 71-77.
doi: 10.1097/mco.0000000000000121
[131]   GAO P, TCHERNYSHYOV I, CHANG T C, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism[J]. Nature, 2009, 458(7239): 762-765.
doi: 10.1038/nature07823
[132]   LIU W, LE A, HANCOCK C, et al. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC[J]. Proc Natl Acad Sci USA, 2012, 109(23): 8983-8988.
doi: 10.1073/pnas.1203244109
[133]   JECK W R, SHARPLESS N E . Detecting and characterizing circular RNAs[J]. Nat Biotechnol, 2014, 32(5): 453-461.
doi: 10.1038/nbt.2890
[134]   HANSEN T B, JENSEN T I, CLAUSEN B H, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441): 384-388.
doi: 10.1038/nature11993
[135]   STOLL L, SOBEL J, RODRIGUEZ-TREJO A, et al. Circular RNAs as novel regulators of β-cell functions in normal and disease conditions[J]. Mol Metab, 2018, 69-83.
doi: 10.1016/j.molmet.2018.01.010
[136]   ZHENG Q, BAO C, GUO W, et al. Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs[J]. Nat Commun, 2016, 7(1): 11215.
doi: 10.1038/ncomms11215
[137]   LIANG G, LIU Z, TAN L, et al. HIF1α-associatedcircDENND4C promotes proliferation of breast cancer cells in hypoxic environment[J]. Anticancer Res, 2017, 37(8): 4337-4343.
doi: 10.21873/anticanres.11827
[138]   DANG R Y, LIU F L, LI Y . Circular RNA hsa_circ_ 0010729 regulates vascular endothelial cell proliferation and apoptosis by targeting the miR-186/HIF-1α axis[J]. Biochem BioPhys Res Commun, 2017, 490(2): 104-110.
doi: 10.1016/j.bbrc.2017.05.164
[139]   XIE H, REN X, XIN S, et al. Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer[J]. Oncotarget, 2016, 7(18): 26680-26691.
doi: 10.18632/oncotarget.8589
[140]   YU C Y, LI T C, WU Y Y, et al. The circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency[J]. Nat Commun, 2017, 8(1): 1149.
doi: 10.1038/s41467-017-01216-w
[141]   ULITSKY I, BARTEL D P . lincRNAs:genomics,evolution,and mechanisms[J]. Cell, 2013, 154(1): 26-46.
doi: 10.1016/j.cell.2013.06.020
[142]   ZOU Z W, MA C, MEDORO L, et al. LncRNA ANRIL is up-regulated in nasopharyngeal carcinoma and promotes the cancer progression via increasing proliferation,reprograming cell glucose metabolism and inducing side-population stem-like cancer cells[J]. Oncotarget, 2016, 7(38): 61741-61754.
doi: 10.18632/oncotarget.11437
[143]   WEI S, FAN Q, YANG L, et al. Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling[J]. Oncology Rep, 2017, 38(3): 1902-1908.
doi: 10.3892/or.2017.5840
[144]   ZHAO Y, LIU Y, LIN L, et al. The lncRNA MACC1- AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1[J]. Mol Cancer, 2018, 17(1): 69.
doi: 10.1186/s12943-018-0820-2
[145]   LI H, LI J, JIA S, et al. miR675 upregulates long noncoding RNA H19 through activating EGR1 in human liver cancer[J]. Oncotarget, 2015, 6(31): 31958-31984.
doi: 10.18632/oncotarget.5579
[146]   MA M Z, ZHANG Y, WENG M Z, et al. Long noncoding RNA GCASPC,a target of miR-17-3p,negatively regulates pyruvate carboxylase–dependent cell proliferation in gallbladder cancer[J]. Cancer Res, 2016, 76(18): 5361-5371.
doi: 10.1158/0008-5472.Can-15-3047
[147]   NGUYEN H B, BABCOCK J T, WELLS C D, et al. LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap[J]. Oncogene, 2013, 32(35): 4100-4109.
doi: 10.1038/onc.2012.431
[148]   CHEN Z, LI J L, LIN S, et al. cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth[J]. J Clin Invest, 2016, 126(6): 2267-2279.
doi: 10.1172/jci85250
[149]   LIU X, XIAO Z D, HAN L, et al. LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress[J]. Nat Cell Biol, 2016, 18(4): 431-442.
doi: 10.1038/ncb3328
[150]   YANG F, ZHANG H, MEI Y, et al. Reciprocal regulation of HIF-1α and lincRNA-p21 modulates the Warburg effect[J]. Mol Cell, 2014, 53(1): 88-100.
doi: 10.1016/j.molcel.2013.11.004
[151]   LUO F, LIU X, LING M, et al. The lncRNA MALAT1,acting through HIF-1α stabilization,enhances arsenite-induced glycolysis in human hepatic L-02 cells[J]. BioChim Biophysica Acta (BBA) - Mol Basis Dis, 2016, 1862(9): 1685-1695.
doi: 10.1016/j.bbadis.2016.06.004
[152]   WU W, HU Q, NIE E, et al. Hypoxia induces H19 expression through direct and indirect Hif-1α activity,promoting oncogenic effects in glioblastoma[J]. Sci Rep, 2017, 7(1): 45029.
doi: 10.1038/srep45029
[153]   LIN A, LI C, XING Z, et al. The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer[J]. Nat Cell Biol, 2016, 18(2): 213-224.
doi: 10.1038/ncb3295
[154]   MADDOCKS O D K, VOUSDEN K H . Metabolic regulation by p53[J]. J Mol Med, 2011, 89(3): 237-245.
doi: 10.1007/s00109-011-0735-5
[155]   WU M, AN J, ZHENG Q, et al. Double mutant P53 (N340Q/L344R) promotes hepatocarcinogenesis through upregulation of Pim1 mediated by PKM2 and LncRNA CUDR[J]. Oncotarget, 2016, 7(41): 66525-66539.
doi: 10.18632/oncotarget.9089
[156]   ZHOU Y, ZHONG Y, WANG Y, et al. Activation of p53 by MEG3 non-coding RNA[J]. J Biol Chem, 2007, 282(34): 24731-24742.
doi: 10.1074/jbc.M702029200
[157]   MAHMOUDI S, HENRIKSSON S, CORCORAN M, et al. Wrap53,a natural p53 antisense transcript required for p53 induction upon DNA damage[J]. Mol Cell, 2009, 33(4): 462-471.
doi: 10.1016/j.molcel.2009.01.028
[158]   TRIPATHI V, SHEN Z, CHAKRABORTY A, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB[J/OL]. PLoS Genet, 2013, 9(3): e1003368.
doi: 10.1371/journal.pgen.1003368
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