N6-Methyladenosine: A Novel RNA Imprint in Human Cancer

Abstract

N 6 -Methyladenosine (m 6 A), a pervasive posttranscriptional modification which is reversible, has been among hotspot issues in the past several years. The balance of intracellular m 6 A levels is dynamically maintained by methyltransferase complex and demethylases. Meanwhile, m 6 A reader proteins specifically recognize modified residues and convey messages so as to set up an efficient and orderly network of m 6 A regulation. The m 6 A mark has proved to affect every step of RNA life cycle, from processing in nucleus to translation or degradation in cytoplasm. Subsequently, disorders in m 6 A methylation are directly related to aberrant RNA metabolism, which results in tumorigenesis and altered drug response. Therefore, uncovering the underlying mechanism of m 6 A in oncogenic transformation and tumor progression seeks opportunities for novel targets in cancer therapy. In this review, we conclude the extensive impact of m 6 A on RNA metabolism and highlight its relevance with human cancer, implicating the far-reaching value in clinical application.

RNA-Binding Proteins as Important Regulators of Long Non-Coding RNAs in Cancer

“…The m6A modification is a reversible and the most abundant RNA modification and stems from the addition of a methyl group to the N-6 position of adenosine by proteins like methyltransferase-like 3 (METTL3), METTL14, and Wilms' tumor 1-associating protein (WTAP) [109,110]. These proteins form a complex that recognizes and interacts with the consensus motif RRACH (R = G/A and H = A/C/U), a motif that is not only frequently found in mRNA but also in lncRNAs, particularly in circRNAs [109,110].…”

“…The m6A modification is a reversible and the most abundant RNA modification and stems from the addition of a methyl group to the N-6 position of adenosine by proteins like methyltransferase-like 3 (METTL3), METTL14, and Wilms' tumor 1-associating protein (WTAP) [109,110]. These proteins form a complex that recognizes and interacts with the consensus motif RRACH (R = G/A and H = A/C/U), a motif that is not only frequently found in mRNA but also in lncRNAs, particularly in circRNAs [109,110]. There are various RBPs, like IGF2BP and the family of YTH domain-containing proteins, that, so to say, read m6A modifications, selectively bind to m6A-modified sites, and subsequently regulate RNA stability, alternative splicing, transport, and translation [109,110].…”

“…These proteins form a complex that recognizes and interacts with the consensus motif RRACH (R = G/A and H = A/C/U), a motif that is not only frequently found in mRNA but also in lncRNAs, particularly in circRNAs [109,110]. There are various RBPs, like IGF2BP and the family of YTH domain-containing proteins, that, so to say, read m6A modifications, selectively bind to m6A-modified sites, and subsequently regulate RNA stability, alternative splicing, transport, and translation [109,110]. Hence, the proteins responsible for generating m6A modifications, the ones reading them, like IGF2BP1, and those removing them, namely fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5), altogether impact not only mRNAs but also lncRNAs on the post-transcriptional level [109][110][111].…”

“…There are various RBPs, like IGF2BP and the family of YTH domain-containing proteins, that, so to say, read m6A modifications, selectively bind to m6A-modified sites, and subsequently regulate RNA stability, alternative splicing, transport, and translation [109,110]. Hence, the proteins responsible for generating m6A modifications, the ones reading them, like IGF2BP1, and those removing them, namely fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5), altogether impact not only mRNAs but also lncRNAs on the post-transcriptional level [109][110][111]. As this includes oncogenes and tumor suppressors alike, aberrant levels of the m6A modification are linked to tumorigenesis and cancer progression, and have thus received quite some interest in research lately [109][110][111].…”

“…Hence, the proteins responsible for generating m6A modifications, the ones reading them, like IGF2BP1, and those removing them, namely fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5), altogether impact not only mRNAs but also lncRNAs on the post-transcriptional level [109][110][111]. As this includes oncogenes and tumor suppressors alike, aberrant levels of the m6A modification are linked to tumorigenesis and cancer progression, and have thus received quite some interest in research lately [109][110][111]. For example, in hepatocellular carcinoma (HCC) the methyltransferase METTL3 is elevated and contributes to tumor progression by generating higher levels of m6A modification in the suppressor of cytokine signaling 2 (SOCS2) mRNA which results in its increased degradation mediated by the YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) [112].…”