FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling 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 catalyse demethylation modification in 3MODIFIER LETTER PRIMEUTR 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 signalling pathway activation and the expression of downstream proteins, leading to tumour metastasis and invasion. We also found the WNT signalling pathway inhibitor ICG-001 can block HOXB13 gene-induced tumour 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.

Automated summary

High expression of FTO in metastatic endometrial cancer promotes tumor metastasis and invasion both in vivo and in vitro by catalyzing demethylation modification in the 3'UTR region of HOXB13 mRNA, leading to activation of the WNT signaling pathway and downstream protein expression. Inhibitor ICG-001 targeting the WNT signaling pathway can block HOXB13 gene-induced tumor metastasis, suggesting a promising molecular intervention. This study sheds light on the relationship between obesity and endometrial cancer pathogenesis, highlighting future research directions.