Diverse molecular functions of m6A mRNA modification in cancer

Abstract

N⁶-methyladenosine (m⁶A), the most prevalent chemical modification found on eukaryotic mRNA, is associated with almost all stages of mRNA metabolism and influences various human diseases. Recent research has implicated the aberrant regulation of m⁶A mRNA modification in many human cancers. An increasing number of studies have revealed that dysregulation of m⁶A-containing gene expression via the abnormal expression of m⁶A methyltransferases, demethylases, or reader proteins is closely associated with tumorigenicity. Notably, the molecular functions and cellular consequences of m⁶A mRNA modification often show opposite results depending on the degree of m⁶A modification in specific mRNA. In this review, we highlight the current progress on the underlying mechanisms of m⁶A modification in mRNA metabolism, particularly the functions of m⁶A writers, erasers, and readers in the context of tumorigenesis.

Fig. 1. An overview of cotranscriptional m⁶A mRNA modification.

Introduction of m⁶A modification is currently suggested to occur cotranscriptionally in the nucleus. Individually transcribing mRNAs illustrate the different modes of cotranscriptional m⁶A modification, including different compositions of associated DNA- and RNA-binding proteins with distinct methylation sites. The thick line represents the coding sequence, and the thin line represents the UTR. The dashed box indicates the heat shock condition.

Fig. 2. Molecular details for m⁶A-mediated mRNA metabolism.

Multiple m⁶A reader proteins dynamically regulate m⁶A-containing mRNA metabolism, including alternative splicing, mRNA export, structural switch, translation, and mRNA stability, depending on the specific m⁶A-bound reader protein. The thick line represents the coding sequence, and the thin line represents the UTR. The dashed box indicates the heat shock condition.

Fig. 3. m⁶A-mediated mRNA regulation in tumorigenesis.

A number of studies have identified the molecular mechanism of m⁶A-mediated mRNA regulation and their effects on tumorigenesis. To date, m⁶A-mediated regulation of translation or mRNA stability has been demonstrated, while the relevance of pre-mRNA splicing or mRNA export remains unclear for specific cancer types.