FTO up‐regulation induced by MYC suppresses tumour progression in Epstein‒Barr virus‐associated gastric cancer

作者：Yunyun Xu, Ting Li, Ao Shen, Xiaoqiong Bao, Jin‐Fei Lin, Li‐Zhen Guo, Qi Meng, Dan‐Yun Ruan, Qihua Zhang, Zhixiang Zuo, Zhao-Lei Zeng · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1505 · 被引用次数：26 · 研究领域：RNA modifications and cancer、Viral-associated cancers and disorders、Ferroptosis and cancer prognosis

BACKGROUND: Epstein-Barr virus-associated gastric cancer (EBVaGC) is regarded as a distinct molecular subtype of GC, accounting for approximately 9% of all GC cases. Clinically, EBVaGC patients are found to have a significantly lower frequency of lymph node metastasis and better prognosis than uninfected individuals. RNA N6-methyladenosine (m6A) modification has an indispensable role in modulating tumour progression in various cancer types. However, its impact on EBVaGC remains unclear. METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and m6A dot blot were conducted to compare the m6A modification levels between EBVaGC and EBV-negative GC (EBVnGC) cells. Western blot, real-time quantitative PCR (RT-qPCR) and immunohistochemistry were applied to explore the underlying mechanism of the reduced m6A modification in EBVaGC. The biological function of fat mass and obesity-associated protein (FTO) was determined in vivo and in vitro. The target genes of FTO were screened by MeRIP-seq, RT-qPCR and Western blot. The m6A binding proteins of target genes were verified by RNA pulldown and RNA immunoprecipitation assays. Chromatin immunoprecipitation and Luciferase report assays were performed to investigate the mechanism how EBV up-regulated FTO expression. RESULTS: M6A demethylase FTO was notably increased in EBVaGC, leading to a reduction in m6A modification, and higher FTO expression was associated with better clinical outcomes. Furthermore, FTO depressed EBVaGC cell...