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

Yiting Sun,Teng Liu,Jing Gao,Lian Liu,Cheng Chen,Meng Wei,Wenbin Yu,Zeyi Zhao,Lanbo Li,Song Li

doi:10.1038/s41419-020-03049-w

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.

Highlights

Gastric cancer is one of the most common malignancies and the third leading cause of cancer-related death worldwide[1]
Elevated m6A is mainly regulated by its “writer” METTL3 in gastric cancer To explore the features of m6A in gastric cancer, we first compared the levels of m6A on total RNAs from 12 pairs of cancerous and adjacent tissues
Due to the remarkable impact of the METTL3/miR-1792 cluster on the AKT/mTOR pathway, we explored whether everolimus, an mTOR inhibitor, could inhibit the onco-promoting role of METTL3

Summary

Introduction

Gastric cancer is one of the most common malignancies and the third leading cause of cancer-related death worldwide[1]. Even among patients who underwent curative resection, 60% suffered recurrences and distant metastasis, with a median overall survival (mOS) of

Methods

Results

Conclusion