Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer

Abnormal RNA methylation and dysregulation of miRNA are frequently occurred in bladder cancer. Melittin is a potential drug candidate for intravesical chemotherapy against bladder cancer. However, the underlying epigenetic mechanism by which melittin-induced anti-tumor effect remains unclear. Here, we showed that melittin selectively induced apoptosis of bladder cancer cells in a METTL3-dependent manner. Ectopic expression of METTL3 significantly blocked melittin-induced apoptosis in vitro and in vivo. MicroRNA-sequence analysis identified miR-146a-5p suppression contributed to the melittin-induced selective antitumor effect. Further investigation revealed that METTL3-guided m6A modification methylated pri-miR-146 at the flanking sequence, which was responsible for the pri-miR-146 maturation. Moreover, NUMB/NOTCH2 axis was identified as a downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of patients with bladder cancer. Our study indicates that METTL3 acts as a fate determinant that controls the sensitivity of bladder cancer cells to melittin treatment. Moreover, METTL3/miR-146a-5p/NUMB/NOTCH2 axis plays an oncogenic role in bladder cancer pathogenesis and could be a potential therapeutic target for recurrent bladder cancer treatment.