FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signaling pathway.

Although many studies have confirmed the relationship between obesity and endometrial cancer (EC), the molecular mechanism between obesity and EC progression has not been elucidated. Overexpression of fat mass and the obesity associated protein FTO leads to weight gain, although recently it has been discovered that FTO can serve as a demethylase which erases N6-methyladenosine (m6A) modification and regulates the metabolization of mRNAs. In this study, we found high expression of FTO in metastatic EC and that this action promote both metastasis and invasion in vivo and in vitro. Mechanistically, FTO can catalyze demethylation modification in 3'UTR region of HOXB13 mRNA, thereby abolishing m6A modification recognition with the YTHDF2 protein. Decreasing HOXB13 mRNA decay and increasing HOXB13 protein expression was accompanied by WNT signaling pathway activation and the expression of downstream proteins, leading to tumor metastasis and invasion. We also found the WNT signaling pathway inhibitor ICG-001 can block HOXB13 gene-induced tumor metastasis, therefore ICG-001 may be a promising molecular intervention. This study provides insight into the relationship between obesity and the pathogenesis of endometrial cancer while highlighting future areas of research.