The mA-independent role of epitranscriptomic factors in cancer.

Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N-methyladenosine (mA) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the mA system, has shown a dramatic impact on cancer development. However, the cellular localization of mA proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that mA methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond mA that still represent an unexplored field. To date novel epigenetic drugs targeting mA modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco-properties of mA effectors beyond mA is required. Here we will provide an overview of methylation-independent functions of the mA players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics.