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ISSN 2097-3497 (Online)
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Volume 37 Issue 9
Sep.  2021
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Article Navigation >  Journal of Clinical Hepatology  > 2021  >  37(9): 2210-2214

Role of N6-methyladenosine in the development and progression of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2021.09.042

  • Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China

Research funding:

National Natural Science Foundation of China (81960125);

Major Research Projects of Innovative Groups of Guizhou Provincial Department of Education (Qian Jiao He KY Zi〔2016〕039)

  • Received Date: 2021-02-01
  • Accepted Date: 2021-03-18
  • Published Date: 2021-09-20
    Abstract
  • Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has relatively high incidence and mortality rates. Abnormal modification of N6-methyladenosine (m6A) may promote the development and progression of HCC. This article describes the structure and function of m6A and summarizes the mechanism of action of methylase complexes which decide the function of m6A in HCC, including methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). It is pointed out that more in-depth studies are needed to clarify the diverse and specific role of methylase complexes in HCC, so as to help them become the new targets for the prevention and treatment of HCC in the future.

     

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    • References(45)
  • [1]
    BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.
    [2]
    HUANG H, WENG H, CHEN J. m(6)A modification in coding and non-coding RNAs: Roles and therapeutic implications in cancer[J]. Cancer Cell, 2020, 37(3): 270-288. DOI: 10.1016/j.ccell.2020.02.004.
    [3]
    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.
    [4]
    LIU N, DAI Q, ZHENG G, et al. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature, 2015, 518(7540): 560-564. DOI: 10.1038/nature14234.
    [5]
    MEYER KD, JAFFREY SR. Rethinking m6A readers, writers, and erasers[J]. Annu Rev Cell Dev Biol, 2017, 33: 319-342. DOI: 10.1146/annurev-cellbio-100616-060758.
    [6]
    PATIL DP, CHEN CK, PICKERING BF, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression[J]. Nature, 2016, 537(7620): 369-373. DOI: 10.1038/nature19342.
    [7]
    WANG X, LU Z, GOMEZ A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014, 505(7481): 117-120. DOI: 10.1038/nature12730.
    [8]
    MOLINIE B, WANG J, LIM KS, et al. m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome[J]. Nat Methods, 2016, 13(8): 692-698. DOI: 10.1038/nmeth.3898.
    [9]
    ALARCÓN CR, LEE H, GOODARZI H, et al. N6-methyladenosine marks primary microRNAs for processing[J]. Nature, 2015, 519(7544): 482-485. DOI: 10.1038/nature14281.
    [10]
    WANG X, ZHAO BS, ROUNDTREE IA, 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.
    [11]
    WANG X, LU Z, GOMEZ A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014, 505(7481): 117-120. DOI: 10.1038/nature12730.
    [12]
    KASOWITZ SD, MA J, ANDERSON SJ, et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development[J]. PLoS Genet, 2018, 14(5): e1007412. DOI: 10.1371/journal.pgen.1007412.
    [13]
    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. DOI: 10.1016/j.cell.2015.08.011.
    [14]
    LIN S, GREGORY RI. Methyltransferases modulate RNA stability in embryonic stem cells[J]. Nat Cell Biol, 2014, 16(2): 129-131. DOI: 10.1038/ncb2914.
    [15]
    KARIKÓ K, BUCKSTEIN M, NI H, et al. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA[J]. Immunity, 2005, 23(2): 165-175. DOI: 10.1016/j.immuni.2005.06.008.
    [16]
    DURBIN AF, WANG C, MARCOTRIGIANO J, et al. RNAs containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling[J]. mBio, 2016, 7(5). DOI: 10.1128/mBio.00833-16.
    [17]
    ZHAO X, YANG Y, SUN BF, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis[J]. Cell Res, 2014, 24(12): 1403-1419. DOI: 10.1038/cr.2014.151.
    [18]
    HUA W, ZHAO Y, JIN X, et al. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition[J]. Gynecol Oncol, 2018, 151(2): 356-365. DOI: 10.1016/j.ygyno.2018.09.015.
    [19]
    LIU X, QIN J, GAO T, et al. YTHDF1 Facilitates the progression of hepatocellular carcinoma by promoting FZD5 mRNA translation in an m6A-dependent manner[J]. Mol Ther Nucleic Acids, 2020, 22: 750-765. DOI: 10.1016/j.omtn.2020.09.036.
    [20]
    LIU GM, ZENG HD, ZHANG CY, et al. Identification of METTL3 as an adverse prognostic biomarker in hepatocellular carcinoma[J]. Dig Dis Sci, 2021, 66(4): 1110-1126. DOI: 10.1007/s10620-020-06260-z.
    [21]
    CHEN M, WEI L, LAW CT, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2[J]. Hepatology, 2018, 67(6): 2254-2270. DOI: 10.1002/hep.29683.
    [22]
    XU H, WANG H, ZHAO W, et al. SUMO1 modification of methyltransferase-like 3 promotes tumor progression via regulating Snail mRNA homeostasis in hepatocellular carcinoma[J]. Theranostics, 2020, 10(13): 5671-5686. DOI: 10.7150/thno.42539.
    [23]
    ZUO X, CHEN Z, GAO W, et al. M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma[J]. J Hematol Oncol, 2020, 13(1): 5. DOI: 10.1186/s13045-019-0839-x.
    [24]
    ZHAO M, JIA M, XIANG Y, et al. METTL3 promotes the progression of hepatocellular carcinoma through m 6 A-mediated up-regulation of microRNA-873-5p[J]. Am J Physiol Gastrointest Liver Physiol, 2020, 319(5): g636. DOI: 10.1152/ajpgi.00161.2020.
    [25]
    LIN Z, NIU Y, WAN A, et al. RNA m6 A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy[J]. EMBO J, 2020, 39(12): e103181. DOI: 10.15252/embj.2019103181.
    [26]
    DOHERTY J, BAEHRECKE EH. Life, death and autophagy[J]. Nat Cell Biol, 2018, 20(10): 1110-1117. DOI: 10.1038/s41556-018-0201-5.
    [27]
    CHEN Y, PENG C, CHEN J, et al. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1[J]. Mol Cancer, 2019, 18(1): 127. DOI: 10.1186/s12943-019-1053-8.
    [28]
    LAN T, LI H, ZHANG D, et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3[J]. Mol Cancer, 2019, 18(1): 186. DOI: 10.1186/s12943-019-1106-z.
    [29]
    CHENG X, LI M, RAO X, et al. KIAA1429 regulates the migration and invasion of hepatocellular carcinoma by altering m6A modification of ID2 mRNA[J]. Onco Targets Ther, 2019, 12: 3421-3428. DOI: 10.2147/OTT.S180954.
    [30]
    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. DOI: 10.1002/hep.28885.
    [31]
    LI Z, LI F, PENG Y, et al. Identification of three m6A-related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma[J]. Cancer Med, 2020, 9(5): 1877-1889. DOI: 10.1002/cam4.2833.
    [32]
    KISHIMOTO T, KOKURA K, NAKADAI T, et al. Overexpression of cysteine sulfinic acid decarboxylase stimulated by hepatocarcinogenesis results in autoantibody production in rats[J]. Cancer Res, 1996, 56(22): 5230-5237. http://hwmaint.cancerres.aacrjournals.org/cgi/reprint/56/22/5230.pdf
    [33]
    JIANG H, ZHANG X, SHEN J, et al. Association between CYP2E1 and GOT2 gene polymorphisms and susceptibility and low-dose N, N-dimethylformamide occupational exposure-induced liver injury[J]. Int Arch Occup Environ Health, 2019, 92(7): 967-975. DOI: 10.1007/s00420-019-01436-1.
    [34]
    YANG H, ZHOU L, SHI Q, et al. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth[J]. EMBO J, 2015, 34(8): 1110-1125. DOI: 10.15252/embj.201591041.
    [35]
    LI J, ZHU L, ZHI Y, et al. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation[J]. Am J Transl Res, 2019, 11(9): 6084-6092. http://www.ncbi.nlm.nih.gov/pubmed/31632576
    [36]
    WANG P, WANG X, ZHENG L, et al. Gene signatures and prognostic values of m6A regulators in hepatocellular carcinoma[J]. Front Genet, 2020, 11: 540186. DOI: 10.3389/fgene.2020.540186.
    [37]
    CHEN Y, ZHAO Y, CHEN J, et al. ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1[J]. Mol Cancer, 2020, 19(1): 123. DOI: 10.1186/s12943-020-01239-w.
    [38]
    MITTENBVHLER MJ, SAEDLER K, NOLTE H, et al. Hepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo[J]. Mol Metab, 2020, 42: 101085. DOI: 10.1016/j.molmet.2020.101085.
    [39]
    LIU X, LIU J, XIAO W, et al. SIRT1 Regulates N6 -Methyladenosine RNA modification in hepatocarcinogenesis by inducing RANBP2-dependent FTO SUMOylation[J]. Hepatology, 2020, 72(6): 2029-2050. DOI: 10.1002/hep.31222.
    [40]
    KONG W, LI X, XU H, et al. Development and validation of a m6A-related gene signature for predicting the prognosis of hepatocellular carcinoma[J]. Biomark Med, 2020, 14(13): 1217-1228. DOI: 10.2217/bmm-2020-0178.
    [41]
    LIN X, CHAI G, WU Y, et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail[J]. Nat Commun, 2019, 10(1): 2065. DOI: 10.1038/s41467-019-09865-9.
    [42]
    ZHANG C, HUANG S, ZHUANG H, et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation[J]. Oncogene, 2020, 39(23): 4507-4518. DOI: 10.1038/s41388-020-1303-7.
    [43]
    YANG Z, LI J, FENG G, et al. MicroRNA-145 modulates N6-methyladenosine levels by targeting the 3'-untranslated mrna region of the N6-methyladenosine binding YTH domain family 2 protein[J]. J Biol Chem, 2017, 292(9): 3614-3623. DOI: 10.1074/jbc.M116.749689.
    [44]
    HOU J, ZHANG H, LIU J, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma[J]. Mol Cancer, 2019, 18(1): 163. DOI: 10.1186/s12943-019-1082-3.
    [45]
    ZHONG L, LIAO D, ZHANG M, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma[J]. Cancer Lett, 2019, 442: 252-261. DOI: 10.1016/j.canlet.2018.11.006.
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