FTO facilitates cancer metastasis by modifying the m(6)A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer

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 integrin family members, which further activated the FAK signaling. CONCLUSION: Our current findings provided valuable insights into the role of FTO-mediated m(6)A demethylation modification in NSCLC metastasis. FTO was identified as a contributor to NSCLC metastasis through the activation of the FAP/integrin/FAK signaling, which may be a potential therapeutic target for NSCLC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-023-01343-6.