METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis

Wei et al. identify that cytoplasmic METTL3 interacts with PABPC1 to facilitate translation of epigenetic factor mRNAs without m(6)A modification to promote tumour progression, suggesting an m(6)A-independent mechanism for this methyltransferase. METTL3 encodes the predominant catalytic enzyme to promote m(6)A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m(6)A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m(6)A modification, but also bind to numerous non-m(6)A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m(6)A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.