The m⁶A-independent role of epitranscriptomic factors in cancer

Protein function alteration and protein mislocalization are cancer hallmarks that drive oncogenesis. N⁶-methyladenosine (m⁶A) deposition mediated by METTL3, METTL16, and METTL5 together with the contribution of additional subunits of the m⁶A system, has shown a dramatic impact on cancer development. However, the cellular localization of m⁶A proteins inside tumor cells has been little studied so far. Interestingly, recent evidence indicates that m⁶A methyltransferases are not always confined to the nucleus, suggesting that epitranscriptomic factors may also have multiple oncogenic roles beyond m⁶A that still represent an unexplored field. To date novel epigenetic drugs targeting m⁶A modifiers, such as METTL3 inhibitors, are entering into clinical trials, therefore, the study of the potential onco-properties of m⁶A effectors beyond m⁶A is required. Here we will provide an overview of methylation-independent functions of the m⁶A players in cancer, describing the molecular mechanisms involved and the future implications for therapeutics.