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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Deciphering the molecular mechanisms of epitranscriptome regulation in cancer

  • Han, Seung Hun (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Choe, Junho (Department of Life Science, College of Natural Sciences, Hanyang University)
  • Received : 2020.09.11
  • Accepted : 2020.11.25
  • Published : 2021.02.28
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Abstract

Post-transcriptional regulation is an indispensable cellular mechanism of gene expression control that dictates various cellular functions and cell fate decisions. Recently, various chemical RNA modifications, termed the "epitranscriptome," have been proposed to play crucial roles in the regulation of post-transcriptional gene expression. To date, more than 170 RNA modifications have been identified in almost all types of RNA. As with DNA modification-mediated control of gene expression, regulation of gene expression via RNA modification is also accomplished by three groups of proteins: writers, readers, and erasers. Several emerging studies have revealed that dysregulation in RNA modification is closely associated with tumorigenesis. Notably, the molecular outcomes of specific RNA modifications often have opposite cellular consequences. In this review, we highlight the current progress in the elucidation of the mechanisms of cancer development due to chemical modifications of various RNA species.

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References

  1. Zhou S, Treloar AE and Lupien M (2016) Emergence of the noncoding cancer genome: a target of genetic and epigenetic alterations. Cancer Discovery 6, 1215-1229 https://doi.org/10.1158/2159-8290.CD-16-0745
  2. Chiba T, Marusawa H and Ushijima T (2012) Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology 143, 550-563 https://doi.org/10.1053/j.gastro.2012.07.009
  3. Yu K, Xiang L, Li S, Wang S, Chen C and Mu H (2019) HIF1alpha promotes prostate cancer progression by increasing ATG5 expression. Anim Cells Syst (Seoul) 23, 326-334 https://doi.org/10.1080/19768354.2019.1658637
  4. Heard E and Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95-109 https://doi.org/10.1016/j.cell.2014.02.045
  5. Zhao Y, Zhao Q, Kaboli PJ et al (2019) m1A regulated genes modulate PI3K/AKT/mTOR and ErbB pathways in gastrointestinal cancer. Transl Oncol 12, 1323-1333 https://doi.org/10.1016/j.tranon.2019.06.007
  6. Tian QH, Zhang MF, Zeng JS et al (2019) METTL1 overexpression is correlated with poor prognosis and promotes hepatocellular carcinoma via PTEN. J Mol Med 97, 1535-1545 https://doi.org/10.1007/s00109-019-01830-9
  7. Yu FX, Zhao B and Guan KL (2015) Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811-828 https://doi.org/10.1016/j.cell.2015.10.044
  8. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE and Jaffrey SR (2012) Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell 149, 1635-1646 https://doi.org/10.1016/j.cell.2012.05.003
  9. Helm M and Motorin Y (2017) Detecting RNA modifications in the epitranscriptome: predict and validate. Nat Rev Genet 18, 275-291 https://doi.org/10.1038/nrg.2016.169
  10. Zhao BS, Roundtree IA and He C (2018) Publisher correction: Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol 19, 808
  11. Fu Y, Dominissini D, Rechavi G and He C (2014) Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet 15, 293-306 https://doi.org/10.1038/nrg3724
  12. Boccaletto P, Machnicka MA, Purta E et al (2018) MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 46, D303-D307 https://doi.org/10.1093/nar/gkx1030
  13. Zhang ZJ, Park E, Lin L and Xing Y (2018) A panoramic view of RNA modifications: exploring new frontiers. Genome Biol 19, 11 https://doi.org/10.1186/s13059-018-1394-4
  14. Shi H, Wei J and He C (2019) Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell 74, 640-650 https://doi.org/10.1016/j.molcel.2019.04.025
  15. Zuo XL, Chen ZQ, Gao W et al (2020) M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma. J Hematol Oncol 13, 5 https://doi.org/10.1186/s13045-019-0839-x
  16. Zheng QL, Gan HL, Yang FL et al (2020) Cytoplasmic m(1)A reader YTHDF3 inhibits trophoblast invasion by downregulation of m(1)A-methylated IGF1R. Cell Discov 6, 12 https://doi.org/10.1038/s41421-020-0144-4
  17. Nachtergaele S and He C (2018) Chemical modifications in the life of an mRNA transcript. Annu Rev Genet 52, 349-372 https://doi.org/10.1146/annurev-genet-120417-031522
  18. Dominissini D, Moshitch-Moshkovitz S, Schwartz S et al (2012) Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201-206 https://doi.org/10.1038/nature11112
  19. Linder B, Grozhik AV, Olarerin-George AO, Meydan C, Mason CE and Jaffrey SR (2015) Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nat Methods 12, 767-772 https://doi.org/10.1038/nmeth.3453
  20. Xiao S, Cao S, Huang Q et al (2019) The RNA N(6)-methyladenosine modification landscape of human fetal tissues. Nat Cell Biol 21, 651-661 https://doi.org/10.1038/s41556-019-0315-4
  21. Wang P, Doxtader KA and Nam Y (2016) Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell 63, 306-317 https://doi.org/10.1016/j.molcel.2016.05.041
  22. Wen J, Lv R, Ma H et al (2018) Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell 69, 1028-1038 e1026 https://doi.org/10.1016/j.molcel.2018.02.015
  23. Ping XL, Sun BF, Wang L et al (2014) Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res 24, 177-189 https://doi.org/10.1038/cr.2014.3
  24. Patil DP, Chen CK, Pickering BF et al (2016) m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 537, 369-373 https://doi.org/10.1038/nature19342
  25. Jia G, Fu Y, Zhao X et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7, 885-887 https://doi.org/10.1038/nchembio.687
  26. Zheng G, Dahl JA, Niu Y et al (2013) ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell 49, 18-29 https://doi.org/10.1016/j.molcel.2012.10.015
  27. Wei J, Liu F, Lu Z et al (2018) Differential m(6)A, m(6)Am, and m(1)A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell 71, 973-985 e975 https://doi.org/10.1016/j.molcel.2018.08.011
  28. Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z and Zhao JC (2014) N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol 16, 191-198 https://doi.org/10.1038/ncb2902
  29. Huang H, Weng H, Sun W et al (2018) Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol 20, 285-295 https://doi.org/10.1038/s41556-018-0045-z
  30. Wang X, Zhao BS, Roundtree IA et al (2015) N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell 161, 1388-1399 https://doi.org/10.1016/j.cell.2015.05.014
  31. Shi H, Wang X, Lu Z et al (2017) YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res 27, 315-328 https://doi.org/10.1038/cr.2017.15
  32. Liu N, Dai Q, Zheng G, He C, Parisien M and Pan T (2015) N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 518, 560-564 https://doi.org/10.1038/nature14234
  33. Meyer KD, Patil DP, Zhou J et al (2015) 5' UTR m(6)A promotes cap-independent translation. Cell 163, 999-1010 https://doi.org/10.1016/j.cell.2015.10.012
  34. Choe J, Lin S, Zhang W et al (2018) mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 561, 556-560 https://doi.org/10.1038/s41586-018-0538-8
  35. Lin S, Choe J, Du P, Triboulet R and Gregory RI (2016) The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell 62, 335-345 https://doi.org/10.1016/j.molcel.2016.03.021
  36. Han SH and Choe J (2020) Diverse molecular functions of m(6)A mRNA modification in cancer. Exp Mol Med 52, 738-749 https://doi.org/10.1038/s12276-020-0432-y
  37. Fazi F and Fatica A (2019) Interplay between N (6)-methyladenosine (m(6)A) and non-coding RNAs in cell development and cancer. Front Cell Dev Biol 7, 116 https://doi.org/10.3389/fcell.2019.00116
  38. Sun T, Wu R and Ming L (2019) The role of m6A RNA methylation in cancer. Biomed Pharmacother 112, 108613 https://doi.org/10.1016/j.biopha.2019.108613
  39. Chen XY, Zhang J and Zhu JS (2019) The role of m(6)A RNA methylation in human cancer. Mol Cancer 18, 103 https://doi.org/10.1186/s12943-019-1033-z
  40. Wang Q, Chen C, Ding Q et al (2020) METTL3-mediated m(6)A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut 69, 1193-1205 https://doi.org/10.1136/gutjnl-2019-319639
  41. Li T, Hu PS, Zuo Z et al (2019) METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer 18, 112 https://doi.org/10.1186/s12943-019-1038-7
  42. Jin H, Ying X, Que B et al (2019) N(6)-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer. EBioMedicine 47, 195-207 https://doi.org/10.1016/j.ebiom.2019.07.068
  43. Barbieri I, Tzelepis K, Pandolfini L et al (2017) Promoterbound METTL3 maintains myeloid leukaemia by m(6)Adependent translation control. Nature 552, 126-131 https://doi.org/10.1038/nature24678
  44. Han J, Wang JZ, Yang X et al (2019) METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer 18, 110 https://doi.org/10.1186/s12943-019-1036-9
  45. Chen XX, Xu M, Xu XN et al (2020) METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer 19, 106 https://doi.org/10.1186/s12943-020-01220-7
  46. Gu CH, Wang ZY, Zhou NC et al (2019) Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N-6-methyladenosine of Notch1. Mol Cancer 18, 168 https://doi.org/10.1186/s12943-019-1084-1
  47. Yang X, Zhang S, He C et al (2020) METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer 19, 46 https://doi.org/10.1186/s12943-020-1146-4
  48. Cohn WE and Volkin E (1951) Nucleoside-5'-phosphates from ribonucleic acid. Nature 167, 483-484 https://doi.org/10.1038/167483a0
  49. Schwartz S, Bernstein DA, Mumbach MR et al (2014) Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell 159, 148-162 https://doi.org/10.1016/j.cell.2014.08.028
  50. Li X, Zhu P, Ma S et al (2015) Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome. Nat Chem Biol 11, 592-597 https://doi.org/10.1038/nchembio.1836
  51. Hoang C and Ferre-D'Amare AR (2001) Cocrystal structure of a tRNA Psi55 pseudouridine synthase: nucleotide flipping by an RNA-modifying enzyme. Cell 107, 929-939 https://doi.org/10.1016/S0092-8674(01)00618-3
  52. De Zoysa MD and Yu YT (2017) Posttranscriptional RNA Pseudouridylation. Enzymes 41, 151-167 https://doi.org/10.1016/bs.enz.2017.02.001
  53. Duan J, Li L, Lu J, Wang W and Ye K (2009) Structural mechanism of substrate RNA recruitment in H/ACA RNA-guided pseudouridine synthase. Mol Cell 34, 427-439 https://doi.org/10.1016/j.molcel.2009.05.005
  54. Rintala-Dempsey AC and Kothe U (2017) Eukaryotic standalone pseudouridine synthases - RNA modifying enzymes and emerging regulators of gene expression? RNA Biol 14, 1185-1196 https://doi.org/10.1080/15476286.2016.1276150
  55. Montanaro L, Brigotti M, Clohessy J et al (2006) Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer. J Pathol 210, 10-18 https://doi.org/10.1002/path.2023
  56. Sieron P, Hader C, Hatina J et al (2009) DKC1 overexpression associated with prostate cancer progression. Br J Cancer 101, 1410-1416 https://doi.org/10.1038/sj.bjc.6605299
  57. Liu B, Zhang J, Huang C and Liu H (2012) Dyskerin overexpression in human hepatocellular carcinoma is associated with advanced clinical stage and poor patient prognosis. PLoS One 7, e43147 https://doi.org/10.1371/journal.pone.0043147
  58. Alawi F, Lin P, Ziober B and Patel R (2011) Correlation of dyskerin expression with active proliferation independent of telomerase. Head Neck 33, 1041-1051 https://doi.org/10.1002/hed.21579
  59. Stockert JA, Gupta A, Herzog B, Yadav SS, Tewari AK and Yadav KK (2019) Predictive value of pseudouridine in prostate cancer. Am J Clin Exp Urol 7, 262-272
  60. Montanaro L, Calienni M, Bertoni S et al (2010) Novel dyskerin-mediated mechanism of p53 inactivation through defective mRNA translation. Cancer Res 70, 4767-4777 https://doi.org/10.1158/0008-5472.CAN-09-4024
  61. McMahon M, Contreras A, Holm M et al (2019) A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS. Elife 8, e48847 https://doi.org/10.7554/eLife.48847
  62. RajBhandary UL, Stuart A, Faulkner RD, Chang SH and Khorana HG (1966) Nucleotide sequence studies on yeast phenylalanine sRNA. Cold Spring Harb Symp Quant Biol 31, 425-434 https://doi.org/10.1101/SQB.1966.031.01.055
  63. Li X, Xiong X, Zhang M et al (2017) Base-resolution mapping reveals distinct m(1)A methylome in nuclearand mitochondrial-encoded transcripts. Mol Cell 68, 993-1005 e1009 https://doi.org/10.1016/j.molcel.2017.10.019
  64. Roundtree IA, Evans ME, Pan T and He C (2017) Dynamic RNA modifications in gene expression regulation. Cell 169, 1187-1200 https://doi.org/10.1016/j.cell.2017.05.045
  65. Li X, Xiong X, Wang K et al (2016) Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol 12, 311-316 https://doi.org/10.1038/nchembio.2040
  66. Liu FG, Clark W, Luo GZ et al (2016) ALKBH1-mediated tRNA demethylation regulates translation. Cell 167, 816-828. e16 https://doi.org/10.1016/j.cell.2016.09.038
  67. Macari F, El-Houfi Y, Boldina G et al (2016) TRM6/61 connects PKCalpha with translational control through tRNAi(Met) stabilization: impact on tumorigenesis. Oncogene 35, 1785-1796 https://doi.org/10.1038/onc.2015.244
  68. Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S et al (2016) The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA. Nature 530, 441-446 https://doi.org/10.1038/nature16998
  69. Seo KW and Kleiner RE (2020) YTHDF2 Recognition of N-1-methyladenosine (m(1)A)-modified RNA is associated with transcript destabilization. Acs Chemical Biol 15, 132-139 https://doi.org/10.1021/acschembio.9b00655
  70. Chen Z, Qi M, Shen B et al (2019) Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res 47, 2533-2545 https://doi.org/10.1093/nar/gky1250
  71. Somme J, Van Laer B, Roovers M, Steyaert J, Versees W and Droogmans L (2014) Characterization of two homologous 2'-O-methyltransferases showing different specificities for their tRNA substrates. RNA 20, 1257-1271 https://doi.org/10.1261/rna.044503.114
  72. Rebane A, Roomere H and Metspalu A (2002) Locations of several novel 2'-O-methylated nucleotides in human 28S rRNA. BMC Mol Biol 3, 1 https://doi.org/10.1186/1471-2199-3-1
  73. Dai Q, Moshitch-Moshkovitz S, Han DL et al (2017) Nm-seq maps 2'-O-methylation sites in human mRNA with base precision (vol 14, pg 695, 2017). Nat Methods 15, 226-227
  74. Dimitrova DG, Teysset L and Carre C (2019) RNA 2'-O-methylation (Nm) modification in human diseases. Genes (Basel) 10, 117 https://doi.org/10.3390/genes10020117
  75. Belanger F, Stepinski J, Darzynkiewicz E and Pelletier J (2010) Characterization of hMTr1, a human Cap1 2'-O-ribose methyltransferase. J Biol Chem 285, 33037-33044 https://doi.org/10.1074/jbc.M110.155283
  76. Werner M, Purta E, Kaminska KH et al (2011) 2'-O-ribose methylation of cap2 in human: function and evolution in a horizontally mobile family. Nucleic Acids Res 39, 4756-4768 https://doi.org/10.1093/nar/gkr038
  77. Ching YP, Zhou HJ, Yuan JG, Qiang BQ, Kung Hf HF and Jin DY (2002) Identification and characterization of FTSJ2, a novel human nucleolar protein homologous to bacterial ribosomal RNA methyltransferase. Genomics 79, 2-6 https://doi.org/10.1006/geno.2001.6670
  78. Koh CM, Gurel B, Sutcliffe S et al (2011) Alterations in nucleolar structure and gene expression programs in prostatic neoplasia are driven by the MYC oncogene. Am J Pathol 178, 1824-1834 https://doi.org/10.1016/j.ajpath.2010.12.040
  79. Su H, Xu T, Ganapathy S et al (2014) Elevated snoRNA biogenesis is essential in breast cancer. Oncogene 33, 1348-1358 https://doi.org/10.1038/onc.2013.89
  80. Marcel V, Ghayad SE, Belin S et al (2013) p53 acts as a safeguard of translational control by regulating fibrillarin and rRNA methylation in cancer. Cancer Cell 24, 318-330 https://doi.org/10.1016/j.ccr.2013.08.013
  81. Squires JE, Patel HR, Nousch M et al (2012) Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res 40, 5023-5033 https://doi.org/10.1093/nar/gks144
  82. Yang X, Yang Y, Sun BF et al (2017) 5-methylcytosine promotes mRNA export-NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res 27, 606-625 https://doi.org/10.1038/cr.2017.55
  83. Motorin Y, Lyko F and Helm M (2010) 5-methylcytosine in RNA: detection, enzymatic formation and biological functions. Nucleic Acids Res 38, 1415-1430 https://doi.org/10.1093/nar/gkp1117
  84. Bohnsack KE, Hobartner C and Bohnsack MT (2019) Eukaryotic 5-methylcytosine (m(5)C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes (Basel) 10, 102 https://doi.org/10.3390/genes10020102
  85. Frye M and Watt FM (2006) The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Current Biol 16, 971-981 https://doi.org/10.1016/j.cub.2006.04.027
  86. Goll MG, Kirpekar F, Maggert KA et al (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395-398 https://doi.org/10.1126/science.1120976
  87. Tuorto F, Liebers R, Musch T et al (2012) RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat Struct Mol Biol 19, 900-905 https://doi.org/10.1038/nsmb.2357
  88. Trixl L and Lusser A (2019) The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip Rev RNA 10, e1510 https://doi.org/10.1002/wrna.1510
  89. Chen X, Li A, Sun BF et al (2019) 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat Cell Biol 21, 978-990 https://doi.org/10.1038/s41556-019-0361-y
  90. Xue S, Xu H, Sun Z et al (2019) Depletion of TRDMT1 affects 5-methylcytosine modification of mRNA and inhibits HEK293 cell proliferation and migration. Biochem Biophys Res Commun 520, 60-66 https://doi.org/10.1016/j.bbrc.2019.09.098
  91. Ramanathan A, Robb GB and Chan SH (2016) mRNA capping: biological functions and applications. Nucleic Acids Res 44, 7511-7526 https://doi.org/10.1093/nar/gkw551
  92. Tomikawa C (2018) 7-methylguanosine modifications in transfer RNA (tRNA). Int J Mol Sci 19, 4080 https://doi.org/10.3390/ijms19124080
  93. Pandolfini L, Barbieri I, Bannister AJ et al (2019) METTL1 promotes let-7 microRNA processing via m7G methylation. Mol Cell 74, 1278-1290 e1279 https://doi.org/10.1016/j.molcel.2019.03.040
  94. Zhang LS, Liu C, Ma HH et al (2019) Transcriptomewide mapping of internal N-7-methylguanosine methylome in mammalian mRNA. Mol Cell 74, 1304-1316.e8 https://doi.org/10.1016/j.molcel.2019.03.036
  95. Malbec L, Zhang T, Chen YS et al (2019) Dynamic methylome of internal mRNA N-7-methylguanosine and its regulatory role in translation. Cell Res 29, 927-941 https://doi.org/10.1038/s41422-019-0230-z
  96. Alexandrov A, Martzen MR and Phizicky EM (2002) Two proteins that form a complex are required for 7-methylguanosine modification of yeast tRNA. RNA 8, 1253-1266 https://doi.org/10.1017/S1355838202024019
  97. Liu Y, Zhang YS, Chi Q, Wang Z and Sun BS (2020) Methyltransferase-like 1 (METTL1) served as a tumor suppressor in colon cancer by activating 7-methyguanosine (m7G) regulated let-7e miRNA/HMGA2 axis. Life Sci 249, 117480 https://doi.org/10.1016/j.lfs.2020.117480
  98. Uddin MB, Wang Z and Yang C (2020) Dysregulations of functional RNA modifications in cancer, cancer stemness and cancer therapeutics. Theranostics 10, 3164-3189 https://doi.org/10.7150/thno.41687
  99. Niu Y, Wan A, Lin Z, Lu X and Wan G (2018) N(6)-methyladenosine modification: a novel pharmacological target for anti-cancer drug development. Acta Pharm Sin B 8, 833-843 https://doi.org/10.1016/j.apsb.2018.06.001
  100. Wilson C, Chen PJ, Miao Z and Liu DR (2020) Programmable m(6)A modification of cellular RNAs with a Cas13-directed methyltransferase. Nat Biotechnol 38, 1431-1440 https://doi.org/10.1038/s41587-020-0572-6