Functions of METTL3 in stem cells and cancer
Francesca Aguilo
Umea University, Sweden
RNA is not only an essential intermediate in the flux of genetic information from DNA to proteins, but rather a molecule that plays crucial roles in the regulation of fundamental cellular processes. Importantly, the dysregulation of certain RNAs has been shown to be implicated in numerous pathological processes, including cancer. The transcriptome is reversibly and dynamically regulated by chemical modifications, adding a new layer of complexity and functionality to the emerging roles of RNAs in health and disease. The impact of these modifications has recently begun to be explored within a new field of study: ‘Epitranscriptomics’.
N6-methyladenosine (m6A) modification is the most prevalent internal modification of eukaryotic messenger RNAs(mRNAs) and plays an important role in the regulation of gene expression. Although m6A deposition is impaired in multiple types of cancer, the specific role of METTL3 –the solely catalytic subunit of the m6A-methylase complex –remains poorly understood in breast cancer. Our findings show that METTL3 enhances the breast cancer phenotype by a novel dual mechanism depending on its sub-cellular localization. We found that the canonical nuclear function of the core of the m6A-methyltransferase complex, which includes METTL3 and its partner METTL14, decorates transcripts that are involved in cell proliferation and migration, thus we could define an m6A-related gene signature specific to breast cancer cells. Additionally,we observed that METTL3 is highly expressed in the cytoplasmic compartment of breast cancer cells from patients where it interacts with the exocyst complex and interferes with vesicle trafficking. Altogether, our findings revealed a novel non-canonical role for METTL3 in the cytoplasm and its adverse consequences for breast cancer growth and metastasis.