N 6 -methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer

N -methyladenosine (m A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m A/DGCR8-dependent mechanism. The m A modification that mediated this process occurred on the A879 locus of pri-miR-17-92. The miR-17-92 cluster activated the AKT/mTOR pathway by targeting PTEN or TMEM127. Compared with those with low levels of METTL3, METTL3-high tumors showed preferred sensitivity to an mTOR inhibitor, everolimus. These results reveal a perspective on epigenetic regulations of non-coding RNA in gastric cancer progression and provide a theoretical rationale for use of everolimus in the treatment of m A/METTL3-high gastric cancer.