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

ABSTRACT: N6-methyladenosine (m6A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m6A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m6A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m6A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m6A/DGCR8-dependent mechanism. The m6A 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 m6A/METTL3-high gastric cancer.

SUBMITTER: Sun Y 

PROVIDER: S-EPMC7547657 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Sun Yiting Y   Li Song S   Yu Wenbin W   Zhao Zeyi Z   Gao Jing J   Chen Cheng C   Wei Meng M   Liu Teng T   Li Lanbo L   Liu Lian L  

Cell death & disease 20201009 10

N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m<sup>6</sup>A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m<sup>6</sup>A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m<sup>6</sup>A facilitated processing of pri-mi  ...[more]

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