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Li, Y.;  Niu, C.;  Wang, N.;  Huang, X.;  Cao, S.;  Cui, S.;  Chen, T.;  Huo, X.;  Zhou, R. m6A Modification and m6A Regulators in Esophageal Cancer. Encyclopedia. Available online: (accessed on 22 June 2024).
Li Y,  Niu C,  Wang N,  Huang X,  Cao S,  Cui S, et al. m6A Modification and m6A Regulators in Esophageal Cancer. Encyclopedia. Available at: Accessed June 22, 2024.
Li, Yuekao, Chaoxu Niu, Na Wang, Xi Huang, Shiru Cao, Saijin Cui, Tianyu Chen, Xiangran Huo, Rongmiao Zhou. "m6A Modification and m6A Regulators in Esophageal Cancer" Encyclopedia, (accessed June 22, 2024).
Li, Y.,  Niu, C.,  Wang, N.,  Huang, X.,  Cao, S.,  Cui, S.,  Chen, T.,  Huo, X., & Zhou, R. (2022, October 28). m6A Modification and m6A Regulators in Esophageal Cancer. In Encyclopedia.
Li, Yuekao, et al. "m6A Modification and m6A Regulators in Esophageal Cancer." Encyclopedia. Web. 28 October, 2022.
m6A Modification and m6A Regulators in Esophageal Cancer

N6-methyladenosine (m6A) refers to the methylation at the N6 position of adenosine, which is considered to be the most prevalent RNA modification.

m6A modification m6A regulators occurrence progression treatment

1. Introduction

N6-methyladenosine (m6A) refers to the methylation at the N6 position of adenosine, which is considered to be the most prevalent RNA modification. Approximately one to two m6A residues are found in every 1000 nucleotides [1][2], and are mainly located in the RRACH sequence (R = A or G, H = A, C, or U) [3][4]. However, not all RRACH motifs are methylated, which suggests that methylation at the N6 position of adenosine is specific and selective [5][6]. N6-methyladenosine occurs in mRNA, rRNA, long non-coding RNA (lncRNA), microRNA (miRNA), circular RNA (circRNA), etc., and is involved in all aspects of RNA metabolism, including RNA processing, nuclear export, stability, translation and degradation. Therefore, m6A modification can participate in various physiological functions, such as tissue development, heat shock response, DNA damage response, circadian clock control and even in carcinogenesis through regulating the expression or structure of the gene [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].
Esophageal cancer (ESCA) is one of the most common malignant tumors, ranking tenth all over the world in 2020 [20]. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the main pathological subtypes of ESCA. Genetic factors and environmental factors interplay to cause the occurrence of ESCA. Smoking, drinking, obesity, etc., are associated with a higher risk of ESCA. Genome-wide association studies and candidate gene association studies both found some susceptible genes of ESCA [21][22][23][24][25]. Furthermore, epigenetic modifications, such as DNA methylation, RNA methylation, histone modifications, et al., also play a critical role in the occurrence and development of ESCA [26][27]. The m6A modification is the most frequent RNA modification, and was firstly identified in 1974 [28]. It was considered as a static process until the fat mass and obesity-associated (FTO) gene was firstly found to be a demethylase in 2010 [29]. With the discovery of FTO and the application of m6A detection technology, m6A modification became a hotspot in the research field of cancer, including ESCA.

2. m6A Modification and m6A Regulators

N6-methyladenosine modification is a dynamic and reversible process. In this process, methyltransferases are responsible for the addition of methyl, while removals of m6A are performed by demethylases. The fate of m6A-modified RNA depends on the protein that recognizes and binds to it. All of the methyltransferases, demethylases and m6A-modified RNA bound proteins that take part in the m6A-modification-associated process belong to m6A regulators.

2.1. Methyltransferases

Methyltransferases are also called “writers”. They catalyze the installation of m6A in the form of a complex, the m6A methyltransferase complex (MTC), which consists of methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), Wilms = tumor-1-associated protein (WTAP), RNA binding protein 15 (RBM15), RNA binding protein 15B (RBM15B), vir like m6Amethyltransferase associated (VIRMA) (also known as KIAA1429), zinc finger CCCH-type containing13 (ZC3H13) and HAKAI. METTL3, METTL14 and WTAP constitute the catalytic core of MTC. METTL3 is the main subunit of MTC, with catalytic activity, and can bind S-adenosylmethionine (SAM) and transfer methyl to the N6 position of adenosine [30]. In addition, cytoplasmic METTL3 can bind to the m6A-modified 3′-untranslated region (UTR) of target mRNA, recruit eukaryotic translation initiation factor 3 subunit H (EIF3H) and enhance the translation efficiency [31][32]. METTL14 forms a stable heterodimer with METTL3 at a 1:1 ratio, stabilizes METTL3 and recognizes and binds to target RNA through its C-terminal RGG repeats [30][33]. With the help of WTAP, the METTL3-METTL14 heterodimer can be located in the nuclear speckle [34]. In addition to the catalytic core of MTC, other components are associated with WTAP and are helpful for the recruitment and localization of the METTL3-METTL14 heterodimer [35][36][37][38][39]. In a WTAP-dependent manner, RBM15/RBM15B correlates with METTL3 and recruits MTC to U-rich regions immediately adjacent to RRACH motifs to catalyze the deposition of m6A [37][40][41]. VIRMA is also a WTAP-associated factor and recruits MTC to 3′-UTR and near the stop codon for m6A catalysis [39]. ZC3H13 connects RBM15/RBM15B with WTAP through its C-terminal structure domain [36][38]. The knockdown of ZC3H13 leads to translocation from the nucleus to cytoplasm for a large proportion of WTAP, VIRMA, HAKAI, METTL3 and METTL14, indicating the important role of ZC3H13 for the nuclear localization of MTC [38]. HAKAI is an E3 ubiquitin-protein ligase, while its role in m6A catalysis is unclear. It is worth noting that m6A deposition depends on transcription. METTL3 and METTL14 form a heterodimer in the cytoplasm and then the heterodimer enters the nucleus with the help of a nuclear localization signal in METTL3. METTL4 can recognize and bind to histone H3 trimethylation at Lys36 (H3k36me3), promote the binding of MTC with RNA polymerase II and transfer MTC to actively transcribing RNAs to install m6A cotranscriptionally [42].
In addition to MTC, there are other methyltransferases, such as methyltransferase-like protein 16 (METTL16), cap-specific adenosine methyltransferase (CAPAM), methyltransferase-like protein 5 (METTL5)/tRNA methyltransferase activator subunit 11-2 (TRMT112) complex and zinc finger CCHC-type containing 4 (ZCCHC4). METTL16 catalyzes m6A deposition in the A43 of U6 small nuclear RNA (snRNA), and is involved in the splicing of RNA [43][44]. The m6A 43 is considered to affect the interaction between snRNA and pre-mRNA and thus regulate the splicing of pre-mRNA [44]. Methionine adenosyl transferase 2A (MAT2A) encodes SAM synthetase. The 3′-UTR hairpins of MAT2A mRNA are substrates of METTL16. The m6A modification of 3′-UTR hairpins influences the splicing of MAT2A pre-mRNA and maintains SAM homeostasis [43][45]. If 2′-O-methyladenosine (Am) is the first transcribed nucleotide of eukaryotic capped mRNAs, CAPAM can recognize it and deposit m6A on it to form a m7GPPPm6Am motif [46][47]. The METTL5/TRMT112 complex and ZCCHC4 are responsible for the methylation of the A1832 of 18S and A4220 of 28S rRNA, respectively [48][49][50].

2.2. Demethylases

Demethylases are termed as “erasers”. The m6A demethylation occurs on nascent transcripts. FTO is the first identified demethylase, and alkB homolog 5 (ALKBH5) is the second one. Ferrous iron and α-ketoglutarate are cofactors of FTO and ALKBH5 [51]. Both FTO and ALKBH5 can remove m6A modification on single RNA and DNA [8][52]. In addition, FTO also can act as demethylase for N6,-2′-O-dimethyladenosine (m6Am) near the N7-methylguanosine (m7G) cap [53].

2.3. m6A RNA Binding Proteins

The fate of m6A-modified RNA depends on the protein that binds to it. This kind of RNA binding protein is referred to as a “reader”. Readers include YT521-B homology (YTH) family proteins, insulin like growth factor 2 mRNA binding proteins (IGF2BPs), heterogeneous nuclear ribonucleoproteins (HNRNPs) and eukaryotic translation initiation factor 3 (EIF3).

3. m6A Modification and Its Effect on Various RNAs in ESCA

A proper m6A level, mainly relying on the appropriate expression and function of m6A regulators, is necessary for sustaining normal bioprocesses. The disruption of the dynamic balance between the installation and removal of m6A modification will lead to the development of diseases, including cancer. An aberrant m6A level associated with the dysregulation of m6A regulators has been reported in a variety of cancers, such as gastric cancer, hepatocellular carcinoma, bladder cancer, etc. [54][55][56]. Nucleotide sequence changes could also result in the gain or loss of m6A sites and contribute to carcinogenesis [57][58]. For example, a base transition from the G to A of rs5746136 in SOD2 led to an increased m6A modification level of SOD2 and an increased binding of HNRNPC with SOD2 through an “m6A switch” mechanism followed by the upregulation of SOD2. The overexpression of SOD2 inhibited the proliferation, migration and invasion of bladder cancer cells, which suggested that SOD2 acted as a tumor suppressor gene for bladder cancer. Thus, the A allele of rs5746136 in SOD2 was associated with a reduced risk of bladder cancer [57]. m6A could deposit on various type of RNA, such as coding RNA and non-coding RNA, participate in all steps of RNA metabolism and post-transcriptionally regulate the expression of the gene (Table 1) [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83].
Table 1. The m6A methylation modified various RNAs in ESCA.

3.1. m6A Modification in ESCA

Most studies revealed that the m6A level was elevated in ESCC tissues and cell lines [73][84][85][86]. However, Cui et al. [83] found lower m6A levels in ESCC cell lines and tissues compared to their counterparts. Some studies indicated that the m6A level could act as a diagnostic and prognostic marker. In gastric cancer, the m6A level might be used to distinguish patients from healthy individuals and predict the prognosis of patients treated with immunotherapy [87][88]. In lung cancer, a higher m6A level in circulating tumor cells than in whole blood cells might be associated with tumor metastasis [89]. Inconsistent results of the m6A level in ESCC suggested that further large sample studies are needed to draw a reliable conclusion.

3.2. The Effect of m6A Modification on mRNA in ESCA

The fate of m6A-modified RNA relies on the m6A reader that binds to it. YTH family proteins, consisting of YTH m6A-binding protein 1 (YTHDF1), YTHDF2, YTHDF3, YTH domain-containing 1 (YTHDC1) and YTHDC2, contain a specific YTH domain, through which, they can recognize and bind to target RNA in an m6A-dependent way [90][91]. YTHDF1 promotes translation initiation and protein synthesis [10]. On the contrary, YTHDF2, the first discovered m6A reader, enhances the degradation of m6A-modified mRNA, either by delivering them to the mRNA decay site or recruiting the CCR4-NOT deadenylase complex to initiate mRNA degradation [9][92]. YTHDF3 interacts with YTHDF1 or YTHDF2, playing opposite roles by promoting mRNA translation or enhancing mRNA degradation [93][94]. YTHDC1 regulates the splicing of the exon and promotes the translocation of m6A-modified mRNA from the nucleus to the cytoplasm [95][96][97]. YTHDC2 elevates the translation efficiency of m6A-modified mRNA; accordingly, the abundance of target mRNA is reduced [98][99]. IGF2BPs, including IGF2BP1, IGF2BP2 and IGF2BP3, enhance mRNA stability [100]. HNRNPs contain HNRNPA2B1, HNRNPC and HNRNPG. HNRNPC and HNRNPG regulate the alternative splicing of mRNA in an m6A-dependent way [13][101]. EIF3 can act as reader of m6A in the 5′-UTR of mRNA [17]. EIF3 participates in almost all steps of translation initiation, which is a rate-limiting process. EIF3 promotes the formation of the 43S pre-initiation complex (PIC), bridges 43S PIC and mRNA bound to the EIF4F complex and takes part in the AUG start codon scanning process [102][103][104][105].
It is generally acknowledged that YTHDF1 plays a facilitating role in translation initiation and protein synthesis [10]. That was true in the study from Zhao et al. [73], which demonstrated that YTHDF1 upregulated the protein level of ERBB2 through recognizing m6A-modified ERBB2 mRNA. Conversely, the knockdown of YTHDF1 enhanced the protein level of HSD17B11, which suggested that YTHDF1 decreased the translation efficiency of m6A-modified HSD17B11 mRNA [74]. YTHDF2 promoted the degradation of APC mRNA and decreased APC expression via binding to m6A-modified APC mRNA [69]. IGF2BP2 enhanced the stability of m6A-modified TK1 and KIF18A mRNA and upregulated their expression [66]. In addition, m6A readers could regulate the stability and expression of their downstream mRNAs through interacting with lncRNA [63][64][65][68][70]. For example, LBX2-AS1 and HNRNPC synergized to increase the stability of ZEB1 and ZEB2 mRNA, upregulated their expression and consequently promoted the migration and epithelial mesenchymal transition (EMT) of ESCC cells [68].

3.3. The Effect of m6A Modification on Non-Coding RNAs in ESCA

Although without a coding ability, non-coding RNAs (ncRNAs), such as miRNA, lncRNA and circRNA, serve a critical role in regulating the expression of the gene.
The miRNAs bind to the 3′-UTR of the target mRNA, and then silence or inhibit the expression of corresponding genes. miRNA biogenesis includes the following steps: firstly, primary miRNA (pri-miRNA) is transcribed from DNA; secondly, pri-miRNA is cleaved into precursor miRNA (pre-miRNA), which requires a microprocessor complex composed of drosha ribonuclease III (DROSHA) and DiGeorge syndrome critical region 8 (DGCR8); thirdly, pre-miRNA is cleaved into mature miRNA. In ESCC, m6A writers and erasers deposit and remove m6A on pri-miRNA, respectively [75][77][78][79]. For instance, METTL3 elevates the m6A level of pri-miR-200-5p, whereas ALKBH5 reduces the m6A level of pri-miR-194-2 [75][78]. A previous study showed that HNRNPA2B1 played a crucial role in the maturation of miRNA through recognizing m6A on pri-miRNA and interacting with DROSHA and DDGCR8 [106]. In ESCC, HNRNPA2B1 promoted the proliferation of ESCC cells through binding to a m6A-modified miR-17-92 cluster and upregulating the expression of a miR-17-92 cluster [79].
m6A modification could also be found on lncRNAs, which might be involved in the regulation of gene expression via influencing the interaction of lncRNAs with RNA binding proteins through an “m6A switch” mechanism or impacting the interaction between lncRNAs and miRNAs [13][107]. In ESCC, the overexpression of FTO significantly reduced the enrichment of m6A at site 2 of the LINC00022 transcript and led to a decrease in the degradation of LINC00022 by YTHDF2 [83]. The study of Wu et al. [81] showed that lncRNA LINC00278 encoded a micropeptide named Yin Yang 1 (YY1)-binding micropeptide (YY1BM), and the binding of YTHDF1 to m6A-modified LINC00278 led to an increased translation of YY1BM. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is located at nuclear speckles (NSs). The MALAT1-m6A-enriched sequence and the binding of YTHDC1 to the m6A of MALAT1 were necessary for maintaining the composition of NSs and migratory capability of ESCC cells [82]. In addition, as mentioned above, lncRNA could interact with m6A readers to regulate the expression of target mRNAs [64][65][68][70].
circRNAs perform different biological functions based on their diverse distribution in cells. Nuclear circRNAs might affect transcription and splicing [108][109]. Cytoplasmic circRNAs might not only absorb miRNAs and alleviate their depression of the target mRNA [110][111] but also might interact with RNA binding proteins and enhance their functional impacts [112][113]. It is worth mentioning that the exon-derived circRNAs might have a protein-encoding ability [114][115]. m6A regulators regulated the expression, distribution and function of circRNAs through installing, removing and recognizing m6A on circRNAs in all sorts of cancers [112][113][116][117][118][119]. In gastric cancer and cervical cancer, METTL14 and ALKBH5 acted as a transmethylase of circORC5 and demethyltransferase of circCCDC134, respectively [116][117]. YTHDC1 facilitated m6A-modified circMET and circNSUN2 exportation from the nucleus to cytoplasm in NONO-TFE3 fusion renal cell carcinoma and colorectal carcinoma, respectively [112][113]. IGF2BP2 interacted with circNSUN2 to increase the stability of HMGA2 mRNA and promote the metastasis of colorectal carcinoma [113]. IGF2BP1 promoted the translation of m6A-modified circMAP3K4 into circMAP3K4-455aa via recognizing m6A modification on circMAP3K4 in hepatocellular carcinoma [118]. Interestingly, m6A modification on circALG1 enhanced its ability as competitive endogenous RNA (ceRNA) of miR-342-5p by increasing its binding to miR-342-5p in colorectal cancer [119]. It is a pity that no study has reported how m6A modification regulates the expression and function of circRNAs during the development and progression of ESCA until now, which provides a direction for future research in ESCA.


  1. Krug, R.M.; Morgan, M.A.; Shatkin, A.J. Influenza viral mRNA contains internal N6-methyladenosine and 5′-terminal 7-methylguanosine in cap structures. J. Virol. 1976, 20, 45–53.
  2. Beemon, K.; Keith, J. Localization of N6-methyladenosine in the Rous sarcoma virus genome. J. Mol. Biol. 1977, 113, 165–179.
  3. Bokar, J.A.; Shambaugh, M.E.; Polayes, D.; Matera, A.G.; Rottman, F.M. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA 1997, 3, 1233–1247.
  4. Wei, C.M.; Moss, B. Nucleotide sequences at the N6-methyladenosine sites of HeLa cell messenger ribonucleic acid. Biochemistry 1977, 16, 1672–1676.
  5. Dominissini, D.; Moshitch-Moshkovitz, S.; Schwartz, S.; Salmon-Divon, M.; Ungar, L.; Osenberg, S.; Cesarkas, K.; Jacob-Hirsch, J.; Amariglio, N.; Kupiec, M.; et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 2012, 485, 201–206.
  6. Meyer, K.D.; Saletore, Y.; Zumbo, P.; Elemento, O.; Mason, C.E.; Jaffrey, S.R. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012, 149, 1635–1646.
  7. Wang, Y.; Li, Y.; Toth, J.I.; Petroski, M.D.; Zhang, Z.; Zhao, J.C. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 2014, 16, 191–198.
  8. Zheng, G.; Dahl, J.A.; Niu, Y.; Fedorcsak, P.; Huang, C.M.; Li, C.J.; Vågbø, C.B.; Shi, Y.; Wang, W.L.; Song, S.H.; et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 2013, 49, 18–29.
  9. Wang, X.; Lu, Z.; Gomez, A.; Hon, G.C.; Yue, Y.; Han, D.; Fu, Y.; Parisien, M.; Dai, Q.; Jia, G.; et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 2014, 505, 117–120.
  10. Wang, X.; Zhao, B.S.; Roundtree, I.A.; Lu, Z.; Han, D.; Ma, H.; Weng, X.; Chen, K.; Shi, H.; He, C. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell 2015, 161, 1388–1399.
  11. Zhao, X.; Yang, Y.; Sun, B.F.; Shi, Y.; Yang, X.; Xiao, W.; Hao, Y.J.; Ping, X.L.; Chen, Y.S.; Wang, W.J.; et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014, 24, 1403–1419.
  12. Chen, T.; Hao, Y.J.; Zhang, Y.; Li, M.M.; Wang, M.; Han, W.; Wu, Y.; Lv, Y.; Hao, J.; Wang, L.; et al. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 2015, 16, 289–301.
  13. Liu, N.; Dai, Q.; Zheng, G.; He, C.; Parisien, M.; Pan, T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature 2015, 518, 560–564.
  14. Alarcón, C.R.; Lee, H.; Goodarzi, H.; Halberg, N.; Tavazoie, S.F. N6-methyladenosine marks primary microRNAs for processing. Nature 2015, 519, 482–485.
  15. Geula, S.; Moshitch-Moshkovitz, S.; Dominissini, D.; Mansour, A.A.; Kol, N.; Salmon-Divon, M.; Hershkovitz, V.; Peer, E.; Mor, N.; Manor, Y.S.; et al. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 2015, 347, 1002–1006.
  16. Zhou, J.; Wan, J.; Gao, X.; Zhang, X.; Jaffrey, S.R.; Qian, S.B. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature 2015, 526, 591–594.
  17. Meyer, K.D.; Patil, D.P.; Zhou, J.; Zinoviev, A.; Skabkin, M.A.; Elemento, O.; Pestova, T.V.; Qian, S.B.; Jaffrey, S.R. 5′ UTR m(6)A Promotes Cap-Independent Translation. Cell 2015, 163, 999–1010.
  18. Xiang, Y.; Laurent, B.; Hsu, C.H.; Nachtergaele, S.; Lu, Z.; Sheng, W.; Xu, C.; Chen, H.; Ouyang, J.; Wang, S.; et al. RNA m(6)A methylation regulates the ultraviolet-induced DNA damage response. Nature 2017, 543, 573–576.
  19. Zhao, B.S.; Wang, X.; Beadell, A.V.; Lu, Z.; Shi, H.; Kuuspalu, A.; Ho, R.K.; He, C. m(6)A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 2017, 542, 475–478.
  20. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249.
  21. Wang, L.D.; Zhou, F.Y.; Li, X.M.; Sun, L.D.; Song, X.; Jin, Y.; Li, J.M.; Kong, G.Q.; Qi, H.; Cui, J.; et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat. Genet. 2010, 42, 759–763.
  22. Wu, C.; Hu, Z.; He, Z.; Jia, W.; Wang, F.; Zhou, Y.; Liu, Z.; Zhan, Q.; Liu, Y.; Yu, D.; et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat. Genet. 2011, 43, 679–684.
  23. Wu, C.; Kraft, P.; Zhai, K.; Chang, J.; Wang, Z.; Li, Y.; Hu, Z.; He, Z.; Jia, W.; Abnet, C.C.; et al. Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions. Nat. Genet. 2012, 44, 1090–1097.
  24. Zhou, R.M.; Li, Y.; Wang, N.; Huang, X.; Cao, S.R.; Shan, B.E. Association of programmed death-1 polymorphisms with the risk and prognosis of esophageal squamous cell carcinoma. Cancer Genet. 2016, 209, 365–375.
  25. Zhou, R.; Li, Y.; Wang, N.; Niu, C.; Huang, X.; Cao, S.; Huo, X. PARP1 rs1136410 C/C genotype associated with an increased risk of esophageal cancer in smokers. Mol. Biol. Rep. 2021, 48, 1485–1491.
  26. Grady, W.M.; Yu, M.; Markowitz, S.D. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021, 160, 690–709.
  27. Cao, W.; Lee, H.; Wu, W.; Zaman, A.; McCorkle, S.; Yan, M.; Chen, J.; Xing, Q.; Sinnott-Armstrong, N.; Xu, H.; et al. Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma. Nat. Commun. 2020, 11, 3675.
  28. Desrosiers, R.; Friderici, K.; Rottman, F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl. Acad. Sci. USA 1974, 71, 3971–3975.
  29. Jia, G.; Fu, Y.; Zhao, X.; Dai, Q.; Zheng, G.; Yang, Y.; Yi, C.; Lindahl, T.; Pan, T.; Yang, Y.G.; et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat. Chem. Biol. 2011, 7, 885–887.
  30. Wang, P.; Doxtader, K.A.; Nam, Y. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol. Cell 2016, 63, 306–317.
  31. Choe, J.; Lin, S.; Zhang, W.; Liu, Q.; Wang, L.; Ramirez-Moya, J.; Du, P.; Kim, W.; Tang, S.; Sliz, P.; et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 2018, 561, 556–560.
  32. Lin, S.; Choe, J.; Du, P.; Triboulet, R.; Gregory, R.I. The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol. Cell 2016, 62, 335–345.
  33. Schöller, E.; Weichmann, F.; Treiber, T.; Ringle, S.; Treiber, N.; Flatley, A.; Feederle, R.; Bruckmann, A.; Meister, G. Interactions, localization, and phosphorylation of the m(6)A generating METTL3-METTL14-WTAP complex. RNA 2018, 24, 499–512.
  34. Ping, X.L.; Sun, B.F.; Wang, L.; Xiao, W.; Yang, X.; Wang, W.J.; Adhikari, S.; Shi, Y.; Lv, Y.; Chen, Y.S.; et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014, 24, 177–189.
  35. Guo, J.; Tang, H.W.; Li, J.; Perrimon, N.; Yan, D. Xio is a component of the Drosophila sex determination pathway and RNA N(6)-methyladenosine methyltransferase complex. Proc. Natl. Acad. Sci. USA 2018, 115, 3674–3679.
  36. Knuckles, P.; Lence, T.; Haussmann, I.U.; Jacob, D.; Kreim, N.; Carl, S.H.; Masiello, I.; Hares, T.; Villaseñor, R.; Hess, D.; et al. Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d. Genes Dev. 2018, 32, 415–429.
  37. Patil, D.P.; Chen, C.K.; Pickering, B.F.; Chow, A.; Jackson, C.; Guttman, M.; Jaffrey, S.R. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 2016, 537, 369–373.
  38. Wen, J.; Lv, R.; Ma, H.; Shen, H.; He, C.; Wang, J.; Jiao, F.; Liu, H.; Yang, P.; Tan, L.; et al. Zc3h13 Regulates Nuclear RNA m(6)A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol. Cell 2018, 69, 1028–1038.e1026.
  39. Yue, Y.; Liu, J.; Cui, X.; Cao, J.; Luo, G.; Zhang, Z.; Cheng, T.; Gao, M.; Shu, X.; Ma, H.; et al. VIRMA mediates preferential m(6)A mRNA methylation in 3′UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018, 4, 10.
  40. Meyer, K.D.; Jaffrey, S.R. Rethinking m(6)A Readers, Writers, and Erasers. Annu. Rev. Cell Dev. Biol. 2017, 33, 319–342.
  41. Kan, L.; Grozhik, A.V.; Vedanayagam, J.; Patil, D.P.; Pang, N.; Lim, K.S.; Huang, Y.C.; Joseph, B.; Lin, C.J.; Despic, V.; et al. The m(6)A pathway facilitates sex determination in Drosophila. Nat. Commun. 2017, 8, 15737.
  42. Huang, H.; Weng, H.; Zhou, K.; Wu, T.; Zhao, B.S.; Sun, M.; Chen, Z.; Deng, X.; Xiao, G.; Auer, F.; et al. Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally. Nature 2019, 567, 414–419.
  43. Pendleton, K.E.; Chen, B.; Liu, K.; Hunter, O.V.; Xie, Y.; Tu, B.P.; Conrad, N.K. The U6 snRNA m(6)A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell 2017, 169, 824–835.e814.
  44. Warda, A.S.; Kretschmer, J.; Hackert, P.; Lenz, C.; Urlaub, H.; Höbartner, C.; Sloan, K.E.; Bohnsack, M.T. Human METTL16 is a N(6)-methyladenosine (m(6)A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Rep. 2017, 18, 2004–2014.
  45. Shima, H.; Matsumoto, M.; Ishigami, Y.; Ebina, M.; Muto, A.; Sato, Y.; Kumagai, S.; Ochiai, K.; Suzuki, T.; Igarashi, K. S-Adenosylmethionine Synthesis Is Regulated by Selective N(6)-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1. Cell Rep. 2017, 21, 3354–3363.
  46. Akichika, S.; Hirano, S.; Shichino, Y.; Suzuki, T.; Nishimasu, H.; Ishitani, R.; Sugita, A.; Hirose, Y.; Iwasaki, S.; Nureki, O.; et al. Cap-specific terminal N (6)-methylation of RNA by an RNA polymerase II-associated methyltransferase. Science 2019, 363, eaav0080.
  47. Sun, H.; Zhang, M.; Li, K.; Bai, D.; Yi, C. Cap-specific, terminal N(6)-methylation by a mammalian m(6)Am methyltransferase. Cell Res. 2019, 29, 80–82.
  48. van Tran, N.; Ernst, F.G.M.; Hawley, B.R.; Zorbas, C.; Ulryck, N.; Hackert, P.; Bohnsack, K.E.; Bohnsack, M.T.; Jaffrey, S.R.; Graille, M.; et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019, 47, 7719–7733.
  49. Pinto, R.; Vågbø, C.B.; Jakobsson, M.E.; Kim, Y.; Baltissen, M.P.; O’Donohue, M.F.; Guzmán, U.H.; Małecki, J.M.; Wu, J.; Kirpekar, F.; et al. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 2020, 48, 830–846.
  50. Ma, H.; Wang, X.; Cai, J.; Dai, Q.; Natchiar, S.K.; Lv, R.; Chen, K.; Lu, Z.; Chen, H.; Shi, Y.G.; et al. N(6-)Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat. Chem. Biol. 2019, 15, 88–94.
  51. Fedeles, B.I.; Singh, V.; Delaney, J.C.; Li, D.; Essigmann, J.M. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond. J. Biol. Chem. 2015, 290, 20734–20742.
  52. Jia, G.; Yang, C.G.; Yang, S.; Jian, X.; Yi, C.; Zhou, Z.; He, C. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 2008, 582, 3313–3319.
  53. Mauer, J.; Luo, X.; Blanjoie, A.; Jiao, X.; Grozhik, A.V.; Patil, D.P.; Linder, B.; Pickering, B.F.; Vasseur, J.J.; Chen, Q.; et al. Reversible methylation of m(6)A(m) in the 5′ cap controls mRNA stability. Nature 2017, 541, 371–375.
  54. Wang, Q.; Chen, C.; Ding, Q.; Zhao, Y.; Wang, Z.; Chen, J.; Jiang, Z.; Zhang, Y.; Xu, G.; Zhang, J.; et al. METTL3-mediated m(6)A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut 2020, 69, 1193–1205.
  55. Hou, J.; Zhang, H.; Liu, J.; Zhao, Z.; Wang, J.; Lu, Z.; Hu, B.; Zhou, J.; Zhao, Z.; Feng, M.; et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol. Cancer 2019, 18, 163.
  56. Gu, C.; Wang, Z.; Zhou, N.; Li, G.; Kou, Y.; Luo, Y.; Wang, Y.; Yang, J.; Tian, F. Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N(6)-methyladenosine of Notch1. Mol. Cancer 2019, 18, 168.
  57. Liu, H.; Gu, J.; Jin, Y.; Yuan, Q.; Ma, G.; Du, M.; Ge, Y.; Qin, C.; Lv, Q.; Fu, G.; et al. Genetic variants in N6-methyladenosine are associated with bladder cancer risk in the Chinese population. Arch. Toxicol. 2021, 95, 299–309.
  58. Tian, J.; Ying, P.; Ke, J.; Zhu, Y.; Yang, Y.; Gong, Y.; Zou, D.; Peng, X.; Yang, N.; Wang, X.; et al. ANKLE1 N(6) -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. Int. J. Cancer 2020, 146, 3281–3293.
  59. Chen, X.; Huang, L.; Yang, T.; Xu, J.; Zhang, C.; Deng, Z.; Yang, X.; Liu, N.; Chen, S.; Lin, S. METTL3 Promotes Esophageal Squamous Cell Carcinoma Metastasis through Enhancing GLS2 Expression. Front. Oncol. 2021, 11, 667451.
  60. Han, H.; Yang, C.; Zhang, S.; Cheng, M.; Guo, S.; Zhu, Y.; Ma, J.; Liang, Y.; Wang, L.; Zheng, S.; et al. METTL3-mediated m(6)A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway. Mol. Ther.-Nucleic Acids 2021, 26, 333–346.
  61. Li, R.; Zeng, L.; Zhao, H.; Deng, J.; Pan, L.; Zhang, S.; Wu, G.; Ye, Y.; Zhang, J.; Su, J.; et al. ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m(6)A-dependent manner. Mol. Ther. J. Am. Soc. Gene Ther. 2022, 30, 1089–1103.
  62. Nagaki, Y.; Motoyama, S.; Yamaguchi, T.; Hoshizaki, M.; Sato, Y.; Sato, T.; Koizumi, Y.; Wakita, A.; Kawakita, Y.; Imai, K.; et al. m(6) A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis. Genes Cells Devoted Mol. Cell. Mech. 2020, 25, 547–561.
  63. Qin, B.; Dong, M.; Wang, Z.; Wan, J.; Xie, Y.; Jiao, Y.; Yan, D. Long non-coding RNA CASC15 facilitates esophageal squamous cell carcinoma tumorigenesis via decreasing SIM2 stability via FTO-mediated demethylation. Oncol. Rep. 2021, 45, 1059–1071.
  64. Wu, D.; He, X.; Wang, W.; Hu, X.; Wang, K.; Wang, M. Long noncoding RNA SNHG12 induces proliferation, migration, epithelial-mesenchymal transition, and stemness of esophageal squamous cell carcinoma cells via post-transcriptional regulation of BMI1 and CTNNB1. Mol. Oncol. 2020, 14, 2332–2351.
  65. Li, Y.; Li, T.; Yang, Y.; Kang, W.; Dong, S.; Cheng, S. YY1-induced upregulation of FOXP4-AS1 and FOXP4 promote the proliferation of esophageal squamous cell carcinoma cells. Cell Biol. Int. 2020, 44, 1447–1457.
  66. Wu, X.; Fan, Y.; Liu, Y.; Shen, B.; Lu, H.; Ma, H. Long Non-Coding RNA CCAT2 Promotes the Development of Esophageal Squamous Cell Carcinoma by Inhibiting miR-200b to Upregulate the IGF2BP2/TK1 Axis. Front. Oncol. 2021, 11, 680642.
  67. Qian, L.X.; Cao, X.; Du, M.Y.; Ma, C.X.; Zhu, H.M.; Peng, Y.; Hu, X.Y.; He, X.; Yin, L. KIF18A knockdown reduces proliferation, migration, invasion and enhances radiosensitivity of esophageal cancer. Biochem. Biophys. Res. Commun. 2021, 557, 192–198.
  68. Zhang, Y.; Chen, W.; Pan, T.; Wang, H.; Zhang, Y.; Li, C. LBX2-AS1 is activated by ZEB1 and promotes the development of esophageal squamous cell carcinoma by interacting with HNRNPC to enhance the stability of ZEB1 and ZEB2 mRNAs. Biochem. Biophys. Res. Commun. 2019, 511, 566–572.
  69. Wang, W.; Shao, F.; Yang, X.; Wang, J.; Zhu, R.; Yang, Y.; Zhao, G.; Guo, D.; Sun, Y.; Wang, J.; et al. METTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N(6)-methyladenosine-dependent YTHDF binding. Nat. Commun. 2021, 12, 3803.
  70. Huang, G.W.; Chen, Q.Q.; Ma, C.C.; Xie, L.H.; Gu, J. linc01305 promotes metastasis and proliferation of esophageal squamous cell carcinoma through interacting with IGF2BP2 and IGF2BP3 to stabilize HTR3A mRNA. Int. J. Biochem. Cell Biol. 2021, 136, 106015.
  71. Wang, Y.; Yu, Z.; Shi, W.; Shen, J.; Guan, Y.; Ni, F. HLA complex P5 upregulation is correlated with poor prognosis and tumor progression in esophageal squamous cell carcinoma. Bioengineered 2022, 13, 9301–9311.
  72. Liao, L.; He, Y.; Li, S.J.; Zhang, G.G.; Yu, W.; Yang, J.; Huang, Z.J.; Zheng, C.C.; He, Q.Y.; Li, Y.; et al. Anti-HIV drug elvitegravir suppresses cancer metastasis via increased proteasomal degradation of m6A methyltransferase METTL3. Cancer Res. 2022, 82, 2444–2457.
  73. Zhao, F.; Ge, F.; Xie, M.; Li, Z.; Zang, C.; Kong, L.; Pu, Y.; Zheng, X.; Tan, Y. FTO mediated ERBB2 demethylation promotes tumor progression in esophageal squamous cell carcinoma cells. Clin. Exp. Metastasis 2022, 39, 623–639.
  74. Duan, X.; Yang, L.; Wang, L.; Liu, Q.; Zhang, K.; Liu, S.; Liu, C.; Gao, Q.; Li, L.; Qin, G.; et al. m6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in esophageal cancer. Cell Biosci. 2022, 12, 60.
  75. Liang, X.; Zhang, Z.; Wang, L.; Zhang, S.; Ren, L.; Li, S.; Xu, J.; Lv, S. Mechanism of methyltransferase like 3 in epithelial-mesenchymal transition process, invasion, and metastasis in esophageal cancer. Bioengineered 2021, 12, 10023–10036.
  76. Liu, T.; Li, P.; Li, J.; Qi, Q.; Sun, Z.; Shi, S.; Xie, Y.; Liu, S.; Wang, Y.; Du, L.; et al. Exosomal and intracellular miR-320b promotes lymphatic metastasis in esophageal squamous cell carcinoma. Mol. Ther. Oncolytics 2021, 23, 163–180.
  77. Liu, Z.; Wu, K.; Gu, S.; Wang, W.; Xie, S.; Lu, T.; Li, L.; Dong, C.; Wang, X.; Zhou, Y. A methyltransferase-like 14/miR-99a-5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2-mediated epigenetic modulation in esophageal squamous cell carcinoma. Clin. Transl. Med. 2021, 11, e545.
  78. Chen, P.; Li, S.; Zhang, K.; Zhao, R.; Cui, J.; Zhou, W.; Liu, Y.; Zhang, L.; Cheng, Y. N(6)-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression. Oncogene 2021, 40, 5600–5612.
  79. Li, K.; Chen, J.; Lou, X.; Li, Y.; Qian, B.; Xu, D.; Wu, Y.; Ma, S.; Zhang, D.; Cui, W. HNRNPA2B1 Affects the Prognosis of Esophageal Cancer by Regulating the miR-17-92 Cluster. Front. Cell Dev. Biol. 2021, 9, 658642.
  80. Xue, J.; Xiao, P.; Yu, X.; Zhang, X. A positive feedback loop between AlkB homolog 5 and miR-193a-3p promotes growth and metastasis in esophageal squamous cell carcinoma. Hum. Cell 2021, 34, 502–514.
  81. Wu, S.; Zhang, L.; Deng, J.; Guo, B.; Li, F.; Wang, Y.; Wu, R.; Zhang, S.; Lu, J.; Zhou, Y. A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell Carcinoma. Cancer Res. 2020, 80, 2790–2803.
  82. Wang, X.; Liu, C.; Zhang, S.; Yan, H.; Zhang, L.; Jiang, A.; Liu, Y.; Feng, Y.; Li, D.; Guo, Y.; et al. N(6)-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles. Dev. Cell 2021, 56, 702–715.e708.
  83. Cui, Y.; Zhang, C.; Ma, S.; Li, Z.; Wang, W.; Li, Y.; Ma, Y.; Fang, J.; Wang, Y.; Cao, W.; et al. RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma. J. Exp. Clin. Cancer Res. CR 2021, 40, 294.
  84. Guo, H.; Wang, B.; Xu, K.; Nie, L.; Fu, Y.; Wang, Z.; Wang, Q.; Wang, S.; Zou, X. m(6)A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1. Front. Oncol. 2020, 10, 553045.
  85. Zou, J.; Zhong, X.; Zhou, X.; Xie, Q.; Zhao, Z.; Guo, X.; Duan, Y. The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma. Biochem. Biophys. Res. Commun. 2021, 580, 48–55.
  86. Li, J.; Liu, H.; Dong, S.; Zhang, Y.; Li, X.; Wang, J. ALKBH5 Is Lowly Expressed in Esophageal Squamous Cell Carcinoma and Inhibits the Malignant Proliferation and Invasion of Tumor Cells. Comput. Math. Methods Med. 2021, 2021, 1001446.
  87. Zhang, B.; Wu, Q.; Li, B.; Wang, D.; Wang, L.; Zhou, Y.L. m(6)A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer. Mol. Cancer 2020, 19, 53.
  88. Ge, L.; Zhang, N.; Chen, Z.; Song, J.; Wu, Y.; Li, Z.; Chen, F.; Wu, J.; Li, D.; Li, J.; et al. Level of N6-Methyladenosine in Peripheral Blood RNA: A Novel Predictive Biomarker for Gastric Cancer. Clin. Chem. 2020, 66, 342–351.
  89. Huang, W.; Qi, C.B.; Lv, S.W.; Xie, M.; Feng, Y.Q.; Huang, W.H.; Yuan, B.F. Determination of DNA and RNA Methylation in Circulating Tumor Cells by Mass Spectrometry. Anal. Chem. 2016, 88, 1378–1384.
  90. Xu, C.; Wang, X.; Liu, K.; Roundtree, I.A.; Tempel, W.; Li, Y.; Lu, Z.; He, C.; Min, J. Structural basis for selective binding of m6A RNA by the YTHDC1 YTH domain. Nat. Chem. Biol. 2014, 10, 927–929.
  91. Zhu, T.; Roundtree, I.A.; Wang, P.; Wang, X.; Wang, L.; Sun, C.; Tian, Y.; Li, J.; He, C.; Xu, Y. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res. 2014, 24, 1493–1496.
  92. Du, H.; Zhao, Y.; He, J.; Zhang, Y.; Xi, H.; Liu, M.; Ma, J.; Wu, L. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat. Commun. 2016, 7, 12626.
  93. Li, A.; Chen, Y.S.; Ping, X.L.; Yang, X.; Xiao, W.; Yang, Y.; Sun, H.Y.; Zhu, Q.; Baidya, P.; Wang, X.; et al. Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res. 2017, 27, 444–447.
  94. Shi, H.; Wang, X.; Lu, Z.; Zhao, B.S.; Ma, H.; Hsu, P.J.; Liu, C.; He, C. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017, 27, 315–328.
  95. Xiao, W.; Adhikari, S.; Dahal, U.; Chen, Y.S.; Hao, Y.J.; Sun, B.F.; Sun, H.Y.; Li, A.; Ping, X.L.; Lai, W.Y.; et al. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol. Cell 2016, 61, 507–519.
  96. Roundtree, I.A.; Luo, G.Z.; Zhang, Z.; Wang, X.; Zhou, T.; Cui, Y.; Sha, J.; Huang, X.; Guerrero, L.; Xie, P.; et al. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. eLife 2017, 6, e31311.
  97. Lesbirel, S.; Viphakone, N.; Parker, M.; Parker, J.; Heath, C.; Sudbery, I.; Wilson, S.A. The m(6)A-methylase complex recruits TREX and regulates mRNA export. Sci. Rep. 2018, 8, 13827.
  98. Wojtas, M.N.; Pandey, R.R.; Mendel, M.; Homolka, D.; Sachidanandam, R.; Pillai, R.S. Regulation of m(6)A Transcripts by the 3′→5′ RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline. Mol. Cell 2017, 68, 374–387.e312.
  99. Hsu, P.J.; Zhu, Y.; Ma, H.; Guo, Y.; Shi, X.; Liu, Y.; Qi, M.; Lu, Z.; Shi, H.; Wang, J.; et al. Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017, 27, 1115–1127.
  100. Huang, H.; Weng, H.; Sun, W.; Qin, X.; Shi, H.; Wu, H.; Zhao, B.S.; Mesquita, A.; Liu, C.; Yuan, C.L.; et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat. Cell Biol. 2018, 20, 285–295.
  101. Liu, N.; Zhou, K.I.; Parisien, M.; Dai, Q.; Diatchenko, L.; Pan, T. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 2017, 45, 6051–6063.
  102. Pestova, T.V.; Kolupaeva, V.G.; Lomakin, I.B.; Pilipenko, E.V.; Shatsky, I.N.; Agol, V.I.; Hellen, C.U. Molecular mechanisms of translation initiation in eukaryotes. Proc. Natl. Acad. Sci. USA 2001, 98, 7029–7036.
  103. Jackson, R.J.; Hellen, C.U.; Pestova, T.V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 2010, 11, 113–127.
  104. Sokabe, M.; Fraser, C.S. Human eukaryotic initiation factor 2 (eIF2)-GTP-Met-tRNAi ternary complex and eIF3 stabilize the 43 S preinitiation complex. J. Biol. Chem. 2014, 289, 31827–31836.
  105. Pestova, T.V.; Kolupaeva, V.G. The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection. Genes Dev. 2002, 16, 2906–2922.
  106. Alarcón, C.R.; Goodarzi, H.; Lee, H.; Liu, X.; Tavazoie, S.; Tavazoie, S.F. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell 2015, 162, 1299–1308.
  107. Yang, D.; Qiao, J.; Wang, G.; Lan, Y.; Li, G.; Guo, X.; Xi, J.; Ye, D.; Zhu, S.; Chen, W.; et al. N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucleic Acids Res. 2018, 46, 3906–3920.
  108. Yang, L.; Han, B.; Zhang, Z.; Wang, S.; Bai, Y.; Zhang, Y.; Tang, Y.; Du, L.; Xu, L.; Wu, F.; et al. Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models. Circulation 2020, 142, 556–574.
  109. Conn, V.M.; Hugouvieux, V.; Nayak, A.; Conos, S.A.; Capovilla, G.; Cildir, G.; Jourdain, A.; Tergaonkar, V.; Schmid, M.; Zubieta, C.; et al. A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat. Plants 2017, 3, 17053.
  110. Thomson, D.W.; Dinger, M.E. Endogenous microRNA sponges: Evidence and controversy. Nat. Rev. Genet. 2016, 17, 272–283.
  111. Hansen, T.B.; Jensen, T.I.; Clausen, B.H.; Bramsen, J.B.; Finsen, B.; Damgaard, C.K.; Kjems, J. Natural RNA circles function as efficient microRNA sponges. Nature 2013, 495, 384–388.
  112. Yang, L.; Chen, Y.; Liu, N.; Lu, Y.; Ma, W.; Yang, Z.; Gan, W.; Li, D. CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3. Mol. Cancer 2022, 21, 23.
  113. Chen, R.X.; Chen, X.; Xia, L.P.; Zhang, J.X.; Pan, Z.Z.; Ma, X.D.; Han, K.; Chen, J.W.; Judde, J.G.; Deas, O.; et al. N(6)-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis. Nat. Commun. 2019, 10, 4695.
  114. Zhou, C.; Molinie, B.; Daneshvar, K.; Pondick, J.V.; Wang, J.; Van Wittenberghe, N.; Xing, Y.; Giallourakis, C.C.; Mullen, A.C. Genome-Wide Maps of m6A circRNAs Identify Widespread and Cell-Type-Specific Methylation Patterns that Are Distinct from mRNAs. Cell Rep. 2017, 20, 2262–2276.
  115. Yang, Y.; Fan, X.; Mao, M.; Song, X.; Wu, P.; Zhang, Y.; Jin, Y.; Yang, Y.; Chen, L.L.; Wang, Y.; et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 2017, 27, 626–641.
  116. Fan, H.N.; Chen, Z.Y.; Chen, X.Y.; Chen, M.; Yi, Y.C.; Zhu, J.S.; Zhang, J. METTL14-mediated m(6)A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis. Mol. Cancer 2022, 21, 51.
  117. Liang, L.; Zhu, Y.; Li, J.; Zeng, J.; Wu, L. ALKBH5-mediated m6A modification of circCCDC134 facilitates cervical cancer metastasis by enhancing HIF1A transcription. J. Exp. Clin. Cancer Res. 2022, 41, 261.
  118. Duan, J.L.; Chen, W.; Xie, J.J.; Zhang, M.L.; Nie, R.C.; Liang, H.; Mei, J.; Han, K.; Xiang, Z.C.; Wang, F.W.; et al. A novel peptide encoded by N6-methyladenosine modified circMAP3K4 prevents apoptosis in hepatocellular carcinoma. Mol. Cancer 2022, 21, 93.
  119. Lin, C.; Ma, M.; Zhang, Y.; Li, L.; Long, F.; Xie, C.; Xiao, H.; Liu, T.; Tian, B.; Yang, K.; et al. The N(6)-methyladenosine modification of circALG1 promotes the metastasis of colorectal cancer mediated by the miR-342-5p/PGF signalling pathway. Mol. Cancer 2022, 21, 80.
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