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

ABSTRACT

BACKGROUND: Emerging evidence suggests the critical roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and tumor progression. However, the role of m6A in non-small cell lung cancer (NSCLC) is still unclear. This study aimed to explore the role of the m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of NSCLC. METHODS: A human m6A 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. M6A-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 m6A 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 m6A 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. Video Abstract.

Emerging evidence suggests the crucial roles of N6-methyladenosine (m6A) RNA modification in tumorigenesis and progression. Nonetheless, the role of m6A in NSCLC remains unclear. The purpose of this study was to investigate the role of m6A demethylase fat mass and obesity-associated protein (FTO) in the tumor metastasis of non-small cell lung cancer (NSCLC). Results illustrated that FTO was upregulated and predicted poor prognosis in NSCLC patients. 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 m6A 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. Our current findings provided valuable insights into the role of FTO-mediated m6A 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.