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

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.

RNA N6-methyladenosine modification in female reproductive biology and pathophysiology

“…In contrast to the tumour-promoting effects of FTO reported in other studies, a study on ovarian cancer confirmed that FTO expression was suppressed in ovarian cancer and that the demethylation activity of FTO could inhibit the stemness characteristics and self-renewal of ovarian tumour stem cells by regulating the cAMP pathway [134]. Similar to the findings of this study, another study confirmed that low FTO expression was associated with higher FIGO staging in ovarian cancer patients and that FTO decreased the m 6 A level and stability of SNAI1 mRNA, leading to downregulation of SNAI1 expression and inhibition of the epithelial-mesenchymal transition [135].…”

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

“…FTO is downregulated in ovarian cancer stem cells and tumours 91 . Downregulation of FTO increases the m6A level in the SNAI1 transcript, enhancing its stability via an IGF2BPs‐dependent manner and promoting epithelial‐to‐mesenchymal transition 92 . FTO inhibits ovarian cancer stem cell self‐renewal by upregulating PDE1C and PDE4B, which subsequently block the cAMP signalling pathway 91 .…”

Roles of RNA Methylations in Cancer Progression, Autophagy, and Anticancer Drug Resistance

“…m6A demethylases removes the m6A methylation group of RNA. FTO is involved in processing of micro RNAs (miRNAs) [ 50 ], as well as RNA stability [ 51 ] and metabolism [ 52 ]. ALKBH5 reduces m6A levels and is involved in mRNA export and RA metabolism [ 53 ].…”