FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2

SIMPLE SUMMARY: Ovarian cancer is the gynaecologic malignant tumour with the highest mortality. Most patients are already in the advanced stage when they are found, and the 5-year survival rate is only 30–40%. Recurrence and metastasis of ovarian cancer are the difficulties of treatment. This study demonstrated for the first time that fat mass and obesity-associated protein (FTO) acts as an m6A demethylase to inhibit epithelial ovarian cancer growth and metastasis. Further, we demonstrated that FTO expression is negatively correlated with the FIGO stage in patients with epithelial ovarian cancer. In addition, we described the regulatory role of FTO-IGF2BP2-SNAI1 in epithelial ovarian cancer progression and provided a novel biomarker and treatment strategy for epithelial ovarian cancer. ABSTRACT: Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial–mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3′ UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.