N6-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer

• Published in: Cell death & disease Vol. 11; no. 10; p. 836
• Main Authors: Sun, Yiting, Li, Song, Yu, Wenbin, Zhao, Zeyi, Gao, Jing, Chen, Cheng, Wei, Meng, Liu, Teng, Li, Lanbo, Liu, Lian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.10.2020
• Subjects: 13/109; 13/51; 13/89; 38/109; 38/77; 45/90; 64/60; 692/308/2056; 692/699/67/1504/1829; 96/95; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Immunology; Life Sciences
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03049-w

N 6 -methyladenosine (m 6 A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m 6 A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m 6 A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m 6 A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m 6 A/DGCR8-dependent mechanism. The m 6 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 6 A/METTL3-high gastric cancer.