FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer

作者：Lirong Gao, Anqi Wang, Yuling Chen, Xin Cai, Yue Li, Jian Zhao, Yang Zhang, Weijie Zhang, Jianjie Zhu, Yuanyuan Zeng, Zeyi Liu, Jian‐An Huang · 发表于：Cell Communication and Signaling · 年份：2023 · DOI：10.1186/s12964-023-01343-6 · 被引用次数：25 · 研究领域：RNA modifications and cancer、Peptidase Inhibition and Analysis、Ubiquitin and proteasome pathways

Abstract Background Emerging evidence suggests the critical roles of N 6 -methyladenosine (m 6 A) RNA modification in tumorigenesis and tumor progression. However, the role of m 6 A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m 6 A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of NSCLC. Methods A human m 6 A epitranscriptomic microarray analysis was used to identify downstream targets of FTO. Quantitative real-time PCR (qRT‒PCR) and western blotting were employed to evaluate the expression levels of FTO and FAP in NSCLC cell lines and tissues. Gain-of-function and loss-of-function assays were conducted in vivo and in vitro to assess the effects of FTO and FAP on NSCLC metastasis. M 6 A-RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), luciferase reporter assays, and RNA stability assays were used to explore the mechanism of FTO action. Co-immunoprecipitation (co-IP) assays were used to determine the mechanism of FAP in NSCLC metastasis. Results FTO was upregulated and predicted poor prognosis in patients with NSCLC. FTO promoted cell migration and invasion in NSCLC, and the FAK inhibitor defactinib (VS6063) suppressed NSCLC metastasis induced by overexpression of FTO. Mechanistically, FTO facilitated NSCLC metastasis by modifying the m 6 A level of FAP in a YTHDF2-dependent manner. Moreover, FTO-mediated metastasis formation depended on the interactions between FAP and in...