Decoding the specificity of m⁶A RNA methylation and its implication in cancer therapy

N6-methyladenosine (m⁶A) is the most abundant endogenous modification in eukaryotic RNAs. It plays important roles in various biological processes and diseases, including cancers. More and more studies have revealed that the deposition of m⁶A is specifically regulated in a context-dependent manner. Here, we review the diverse mechanisms that determine the topology of m⁶A along RNAs and the cell-type-specific m⁶A methylomes. The exon junction complex (EJC) as well as histone modifications play important roles in determining the topological distribution of m⁶A along nascent RNAs, while the transcription factors and RNA-binding proteins, which usually bind specific DNAs and RNAs in a cell-type-specific manner, largely account for the cell-type-specific m⁶A methylomes. Due to the lack of specificity of m⁶A writers and readers, there are still challenges to target the core m⁶A machinery for cancer therapies. Therefore, understanding the mechanisms underlying the specificity of m⁶A modifications in cancers would be important for future cancer therapies through m⁶A intervention.