N6-甲基腺嘌呤与癌症的研究进展

doi:10.11904/j.issn.1002-3070.2019.04.013

摘要/Abstract

摘要： N6-甲基腺嘌呤(m⁶A)作为一种主要的RNA甲基化修饰,通过多种机制影响人类癌症的发生和发展。m⁶A修饰影响RNA代谢的多个方面,从RNA加工、核输出、RNA翻译到衰变。在这篇综述中,介绍了m⁶A甲基化基本概念,m⁶A甲基转移酶复合物和m⁶A去甲基化酶在几种主要癌症中的调控作用和一些作为m⁶A结合蛋白的蛋白质执行的m⁶A修饰的生物学功能。此外,还讨论了m⁶A甲基化的双重作用以及它在临床应用中的潜力。

关键词: N6-甲基腺嘌呤(m⁶A), 甲基转移酶, 去甲基化酶, 癌症, 表观遗传学

Abstract: N6-methyladenine(m⁶A),a major RNA methylation modification,affects the development and progression of human cancer through a variety of mechanisms.The m⁶A modification also affects multiple aspects of RNA metabolism,ranging from RNA processing,nuclear export,RNA translation to decay.In this review,the basic concepts of m⁶A methylation,regulation of m⁶A methyltransferase complex and m⁶A demethylases in several cancers and some m⁶A performed the biological function of the modification as m⁶A-binding proteins are introduced.In addition,the dual role of m⁶A methylation and its potential in clinical application are summarized in this review.

Key words: N6-methyladenine(m⁶A), Methyltransferases, Demethylases, Cancer, Epigenetics

中图分类号:

张玫茵娄阁. N6-甲基腺嘌呤与癌症的研究进展[J]. 实用肿瘤学杂志, 2019, 33(4): 357-360.

ZHANG Meiyin, LOU Ge. Advances progress of N6-methyladenine and cancer[J]. Journal of Practical Oncology, 2019, 33(4): 357-360.

参考文献

1 Strahl BD,Allis CD.The language of covalent histone modifications[J].Nature,2000,403(6765):41-45.
2 Cantara WA,Crain PF,Rozenski J,et al.The RNA modification database,RNAMDB:2011 update[J].Nucleic Acids Res,2011,39:195-201.
3 Chen T,Hao YJ,Zhang Y,et al.m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency[J].Cell Stem Cell,2015,16(3):289-301.
4 Alarcón CR,Goodarzi H,Lee H,et al.HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events[J].Cell,2015,162(6):1299-1308.
5 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.
6 Dominissini D,Moshitch-Moshkovitz S,Schwartz S,et al.Topology of the human and mouse m(6)A RNA methylomes revealed by m(6)A-seq[J].Nature,2012,485:201-208.
7 Liu J,Yue Y,Han D,et al.A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J].Nat Chem Biol,2014,10(2):93-95.
8 Lin S,Choe J,Du P,et al.The m(6)A methyltransferase METTL3 promotes translation in human cancer cells[J].Mol Cell,2017,62(3):335-345.
9 Du M,Zhang Y,Mao Y,et al.MiR-33a sup-presses proliferation of NSCLC cells via tar-geting METTL3 mRNA[J].Biochem Biophys Res Commun,2017,482(4):582-589.
10 Cui Q,Shi H,Ye P,et al.m⁶A RNA methylation regulates the self re-newal and tumorigenesis of glioblastoma stem cells[J].Cell,2017,18(11):2622-2634.
11 Vu LP,Pickering BF,Cheng Y,et al.The N6-methyladenosine(m⁶A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells[J].Nat Med,2017,23(11):1369-1376.
12 Weng H,Huang H,Wu H,et al.METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m⁶A modification[J].Cell Stem Cell,2018,22(2):191-205.
13 Wang X,Li Z,Kong B,et al.Reduced m⁶A mRNA methylation is correlated with the progression of human cervical cancer[J].Oncotarget,2017,8(58):98918-98930.
14 Li X,Tang J,Huang W,et al.The m⁶A methyltransferase METTL3:acting as a tumor suppressor in renal cell carcinoma[J].Oncotarget,2017,8(56):96103-96116.
15 Zheng G,Dahl JA,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.
16 Ma JZ,Yang F,Zhou CC,et al.METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary microRNA processing[J].Hepatology,2017,65(2):529-543.
17 Wang J,Muntean AG,Hess JL.ECSASB2 mediates MLL degradation during hematopoietic differentiation[J].Blood,2012,119(5):1151-1161.
18 李毅鹏,张鑫宇,吕涵柠,等.MLLT6在白血病中的研究进展[J].实用肿瘤学杂志,2018,32(2):135-139.
19 Zhang S,Zhao BS,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.
20 Zhang C,Zhi WI,Lu H,et al.Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217-and ALKBH5-mediated modulation of RNA methylation in breast cancer cells[J].Oncotarget,2016,7(40):64527-64542.
21 Du H,Zhao Y,He J,et al.YTHDF2 destabilizes m⁶A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex[J].Nat Commun,2016,7:12626.
22 Shi H,Wang X,Lu Z,et al.YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA[J].Cell Res,2017,27(3):315.
23 Li A,Chen YS,Ping XL,et al.Cytoplasmic m⁶A reader YTHDF3 promotes mRNA translation[J].Cell Res,2017,27(3):444-447.
24 Patil DP,Chen CK,Pickering BF,et al.m⁶A RNA methylation promotes XIST-mediated transcriptional repression[J].Nature,2016,537(7620):369-373.
25 Xiao W,Adhikari S,Dahal U,et al.Nuclear m⁶A reader YTHDC1 regulates mRNA splicing[J].Mol Cell,2016,61(4):507-519.
26 Roost C,Lynch SR,Batista PJ,et al.Structure and thermodynamics of N6-methyladenosine in RNA:a spring-loaded base modification[J].J Am Chem Soc,2015,137(5):2107-2115.
27 Spitale RC,Flynn RA,Zhang QC,et al.Structural imprints in vivo decode RNA regulatory mechanisms[J].Nature,2015,519(7544):486-490.
28 Zhou KI,Parisien M,Dai Q,et al.N6-methyladenosine modification in a long noncoding RNA hairpin predisposes its conformation to protein binding[J].J Mol Biol,2016,428:822-833.
29 Liu N,Zhou KI,Parisien M,et al.N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein[J].Nucleic Acids Res,2017,45(10):6051-6063.
30 Xu C,Liu K,Ahmed H,et al.Structural basis for the discriminative recognition of N6-methyladenosine RNA by the human YT521-B homology domain family of proteins[J].J Biol Chem,2015,290(41):24902-24913.
31 Tanabe A,Tanikawa K,Tsunetomi M,et al.RNA helicase YTHDC2 promotes cancer metastasis via the enhancement of the efficiency by which HIF-1a mRNA is translated[J].Cancer Lett,2016,376(1):34-42.
32 Nishizawa Y,Konno M,Asai A,et al.Oncogene c-Myc promotes epitranscriptome m⁶A reader YTHDF1 expression in colorectal cancer[J].Oncotarget,2018,9(7):7476-7486.

[1]	石小康, 丁佑铭, 汪斌, 余斌, 徐雨. UBE2T在原发性肝癌中的表达及临床意义[J]. 实用肿瘤学杂志, 2019, 33(2): 128-133.
[2]	马超(综述), 王国年(审校). 麻醉药物对围术期癌症患者免疫功能的影响[J]. 实用肿瘤学杂志, 2018, 32(3): 285-288.
[3]	张中民, 庞达. 长链非编码RNA调控癌症细胞信号通路的研究进展[J]. 实用肿瘤学杂志, 2018, 32(2): 184-188.
[4]	赵倩妤, 孙轶华. 拉曼光谱在癌症组织学诊断中的研究进展[J]. 实用肿瘤学杂志, 2018, 32(1): 92-96.
[5]	顾秀瑛，顾晓芬，朱俊宇，周天虹，朱琳. 2014-2016年乌鲁木齐市9265例城市居民肺癌筛查结果分析[J]. 实用肿瘤学杂志, 2017, 31(3): 242-245.
[6]	李根英，综述，张云艳，审校. MTBP与癌症的研究进展[J]. 实用肿瘤学杂志, 2016, 30(6): 560-562.
[7]	周海平, 李水富, 张延红, 王峻巍, 常琳, 高晓波, 陈万青. 癌症预防经济状况分析[J]. 实用肿瘤学杂志, 2016, 30(3): 249-252.
[8]	孙惠昕,陈王洋,宋冰冰. 黑龙江省2013—2014年度城市癌症筛查分析[J]. 实用肿瘤学杂志, 2015, 29(4): 315-318.
[9]	吕研¹, 李文鑫¹, 李剑¹综述, 徐向英^1,2审校. 非小细胞肺癌放化疗后局部复发再程放疗的研究进展[J]. 实用肿瘤学杂志, 2015, 29(3): 259-262.
[10]	刘谦,王桂茹. 保护治疗是根除癌症卫士和新医学模式的探讨[J]. 实用肿瘤学杂志, 2013, 27(3): 285-288.
[11]	徐骁盟, 韩晓冬. 癌症过度诊疗及其后果的研究进展[J]. 实用肿瘤学杂志, 2012, 26(6): 550-555.
[12]	陈王洋, 宋冰冰, 杨凤娟, 孙惠昕, 谭秀芝, 付美倩. 黑龙江省尚志市2009年恶性肿瘤的发病和死亡情况分析[J]. 实用肿瘤学杂志, 2012, 26(6): 506-510.
[13]	郝慧婷, 彭士云. 降糖药物二甲双胍在癌症防治方面的新用途[J]. 实用肿瘤学杂志, 2012, 26(5): 477-480.
[14]	沈倩, 尹玉平, 于世英. 165例癌痛患者癌症相关神经病理性疼痛的诊疗现状调查[J]. 实用肿瘤学杂志, 2012, 26(4): 343-347.
[15]	刘海英, 曹国芬. 抗癌药物输液反应的诊断与处置[J]. 实用肿瘤学杂志, 2010, 24(5): 466-469.