Aberrant Regulation of mRNA m⁶A Modification in Cancer Development

Abstract

N⁶-methyladenosine (m⁶A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs). The m⁶A modification in RNA can be catalyzed by methyltransferases, or removed by demethylases, which are termed m⁶A writers and erasers, respectively. Selective recognition and binding by distinct m⁶A reader proteins lead mRNA to divergent destinies. m⁶A has been reported to influence almost every stage of mRNA metabolism and to regulate multiple biological processes. Accumulating evidence strongly supports the correlation between aberrant cellular m⁶A level and cancer. We summarize here that deregulation of m⁶A modification, resulting from aberrant expression or function of m⁶A writers, erasers, readers or some other protein factors, is associated with carcinogenesis and cancer progression. Understanding the regulation and functional mechanism of mRNA m⁶A modification in cancer development may help in developing novel and efficient strategies for the diagnosis, prognosis and treatment of human cancers.

Keywords: cancer development; m6A; m6A eraser; m6A reader; m6A writer.

Figure 1

The writer, eraser, and direct reader proteins of N⁶-methyladenosine (m⁶A). m⁶A modification is dynamically regulated by writers (METTL3 or METTL14) and erasers (fat mass and obesity-associated (FTO) or ALKBH5), both of which are localized primarily in the nucleus. In the nucleus, m⁶A can be recognized and directly bound by m⁶A readers YTHDC1, HNRNPA2B1, andIGF2BP1/2/3. In the cytoplasm, m⁶A can be recognized and directly bound by m⁶A readers YTHDF1/2/3, YTHDC2, eIF3, and IGF2BP1/2/3. Recognition and binding of m⁶A by different readers in the nucleus or cytoplasm mediate divergent biological functions. WTAP, Wilms’ tumor 1-associating protein.