Novel insights into the interplay between m6A modification and noncoding RNAs in cancer

N6-methyladenosine (m6A) is one of the most common RNA modifications in eukaryotes, mainly in messenger RNA (mRNA). Increasing evidence shows that m6A methylation modification acts an essential role in various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs and circRNAs, are known to participate in regulating cell differentiation, angiogenesis, immune response, inflammatory response and carcinogenesis. m6A regulators, such as METTL3, ALKBH5 and IGF2BP1 have been reported to execute a m6A-dependent modification of ncRNAs involved in carcinogenesis. Meanwhile, ncRNAs can target or modulate m6A regulators to influence cancer development. In this review, we provide an insight into the interplay between m6A modification and ncRNAs in cancer.


Introduction
Up to now, more than 100 kinds of RNA modifications have been confirmed [1]. Among them, m 6 A RNA methylation is one of the most thoroughly studied modifications. m 6 A RNA modification occurs by methylation of the sixth N atom of adenine (A) in mRNAs or ncRNAs [2]. m 6 A modification sites tend to be found in the stop codons and 3′-Untranslated region (3′-UTR) of mRNA with a typical consensus sequence RRACH (R = G or A and H = A, C, or U) [3,4]. Accumulating data show that m 6 A RNA methylation acts by modulating circadian rhythm, gene expression, cell differentiation, stress response, inflammatory response, and carcinogenesis [5][6][7][8][9][10]. According to the global cancer statistics, there were estimated 18.1 million new cases and 9.6 million deaths in 2018 [11]. Recent studies have shown that m 6 A modification acts a vital role in the diagnosis, treatment and prognosis of cancer patients as well as in carcinogenesis. It also regulates fly sex, virus genome, meiosis of yeast, tissue differentiation, germination, and collateral generation of Arabidopsis [12][13][14][15].
Noncoding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) act pivotal roles in cancer [16][17][18]. m 6 A modification can affect ncRNA splicing and maturation involved in carcinogenesis (Table 1). In this review, we summarize the latest progress about the interplay between m 6 A modification and ncRNAs in cancer.

Tumor invasion and metastasis
METTL14 promotes the maturation of pri-miR-126 and suppresses the invasion and metastasis of hepatocellular  [48]. METTL3 facilitates the maturation of pri-miR-1246 to enhance the metastasis of colorectal cancer (CRC) [49]. METTL3 also accelerates the maturation of miR-143-3p, leading to the formation of METTL3/miR-143-3p/vasohibin-1 axis to favor the metastasis of lung cancers [50].

m 6 A modification of lncRNAs in cancer
LncRNAs, a subgroup of non-coding RNAs over 200 nucleotides in length can be modified by m 6 A methylation in cancer (Fig. 3). m 6 A methylation facilitates lncRNA X-inactive specific transcript (XIST)-mediated transcriptional repression [51][52][53]. YTHDC1 preferentially recognizes the m 6 A residues of XIST and RBM15/15B and participates in XISTmediated gene silencing [53]. However, RBM15/m 6 A-MTase complex is reported to act a minor role in XIST-mediated gene silencing [54]. YTHDF2 recognizes m 6 A methylation site of lnc-Dpf3 to promote its degradation and enhances the binding of lnc-Dpf3 with hypoxia-inducible factor 1-alpha (HIF-1α), leading to the suppression of the glycolysis and migration of dendritic cells [55]. METTL3 can modify metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) to form the METTL3/MALAT1/ miR-145/focal adhesion kinase (FAK) axis, contributing to the aggravation of renal fibrogenesis in obstructive nephropathy [56].

Tumor proliferation and tumorigenesis
ALKBH5 has been found upregulated in glioblastoma and prompts the proliferation of glioblastoma stem-like cells (GSCs). A lncRNA antisense to forkhead box M1 (FOXM1-AS) promotes the interaction of ALKBH5 with forkhead box M1 (FOXM1) nascent transcripts to increase FOXM1 expression and GSCs tumorigenesis [57]. LncRNA Differentiation antagonizing non-protein coding RNA (DANCR) contributes to the tumorigenesis of multiple cancers [58,59]. IGF2BP2 serves as an m 6 A reader to modify DANCR and favors the oncogenicity of pancreatic cancer [60]. MALAT1, the first lncRNA to be found associated with lung cancer, possesses a triple helix structure at its 3'end [61][62][63]. METTL16 interacts directly with MALAT1 triple helix and promotes cancer cell proliferation [64].

m 6 A modification of circRNAs in cancer
CircRNAs, a novel subset of ncRNAs generated by backsplicing, play a crucial role in protein translation [73]. METTL3 and YTHDC1 are associated with the metabolism of circular RNA zinc finger protein 609 (circ-ZNF609) and promote its production [74]. Minigenes of ribosomes-circRNAs (Ribo-circRNAs) can facilitate protein translation in drosophila heads and circ-ZNF609 boosts protein translation and myoblasts cell proliferation [75,76]. m 6 A methylation has been reported to affect protein translation of cricRNAs [77,78]. m 6 A motifs are enriched in circRNAs, and a single m 6 A site is regarded as a trigger to initiate the translation of cir-cRNAs. m 6 A regulators METTL3/14, FTO, YTHDF3, and initiation factor eIF4G2 are involved in m 6 A-driven protein translation [78]. Mammalian cells can recognize the m 6 A modification on circRNAs to inhibit innate immunity by abrogating immune gene activation and adjuvant activity [79].
In addition, the dysregulation of circRNAs is associated with the progression of multiple cancers, such as breast cancer, gastric cancer (GC), gallbladder cancer and cervical cancer [80][81][82][83]. YTHDC1 interacts with circRNA NOP2/Sun RNA methyltransferase 2 (cir-cNSUN2) to facilitate its cytoplasmic export, which leads to colorectal liver metastasis by forming a circNUSN2/ IGF2BP2/high mobility group AT-hook 2 (HMGA2) RNA-protein ternary complex in the cytoplasm [84]. m 6 A modification can be involved in the progression of GC by regulating circRNA poliovirus receptor-related 3 (circPVRL3) [85].
Clinical application of m 6 A methylation in cancer m 6 A methylation serves as new biomarkers for diagnosis and prognosis in cancer. m 6 A regulators METTL3, YTHDC2 and HNRNPC are used to predict the prognosis in patients with HNSCC [105]. Upregulated METT L3/FTO or downregulated YTHDF2 and METTL14 can indicate a poor survival in GC, CRC, and HCC [48,70,106]. Low expression of METTL14 is associated with tumor differentiation, clinical stage, and microvascular invasion [48]. Low expression of ALKBH5 or FTO predicts an unfavorable marker in lung cancer and HCC [107,108]. IGF2BP2 is considered as a prognostic marker in pancreatic cancer, esophagogastric junction adenocarcinoma and CRC [60,109,110]. m 6 A methylation also participates in drug resistance and cancer treatment. METTL3 stabilizes YAP and Rho GTPase activating protein 5 (ARHGAP5) to induce cisplatin resistance in NSCLC and in GC [69,111]. HNRN PA2B1 is overexpressed in tamoxifen-resistant breast cancer and reduces 4-hydroxytamoxifen sensitivity [112]. In addition to METTL3 and METTL14, FTO and YTHDF2 are overexpressed in AML [26,27,113,114]. A recent study shows that FTO inhibitor (FB23) and its derivative (FB23-2) promote myeloid differentiation and apoptosis in AML by targeting FTO [115]. m 6 A methylation is also involved in estimating tumor microenvironment and TME infiltration characterization so as to provide insights into an effective immunotherapy for cancer [116]. YTHDF2 is correlated with inflammation infiltration, vascular reconstruction and distant metastasis and predicts a poor prognosis in HCC [117].
In summary, the role of m 6 A modification in clinical application has been widely validated. As for the core members of m 6 A methylation, METTL3/14 exert their functions in many biological processes. METTL3/14 can be regarded as the most important and promising m 6 A regulator and arouse our attention about their modifications on ncRNAs and the clinical application in cancer diagnosis.

Conclusions and perspectives
Accumulating studies have been focused on how m 6 A methylation modifies the stability, splicing and translation of ncRNAs or ncRNAs regulate m 6 A regulators in cancer. The interaction between m 6 A methylation and ncRNAs can impact the different life activities including HCC hepatocellular cancer, GC gastric cancer, CRC colorectal cancer, LUAD lung adenocarcinoma, NSCLC non-small cell lung cancer cancer cell proliferation, invasion and metastasis. As for the clinical application of m 6 A methylation, they can be regarded as the potential targets for cancer diagnosis, prognosis and treatment. The latest findings show that lncRNA long intergenic non-protein coding RNA 266-1 (LINC00266-1) interacts with IGF2BP1 by encoding a 71-amino acid peptide, named RNA-binding regulatory peptide, thereby promoting tumorigenesis [118]. However, the specific binding sites between m 6 A methylation and ncRNAs need be further investigated. Authors' contributions JZ and JSZ designed this study and YCY drafted the manuscript. YCY and XYC collected the data and conducted the picture processing. JZ revised the paper and all authors read and approved the final manuscript.

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