METTL3-Mediated Regulation of TERT Expression in the Pathogenesis of Ovarian Endometriosis

Abstract

Endometriosis is a complex and poorly understood disease that greatly reduces the quality of life in women who suffer from it. Increased levels of human telomerase reverse transcriptase (TERT) mRNA and telomerase activity have been detected in the endometrium of such patients, but the exact role played by TERT and the biological mechanisms accompanying this phenomenon are not well defined. We examined TERT expression in ectopic endometrial, eutopic endometrial, and normal endometrial tissues. Human endometrial stromal cells were employed to explore the effects of TERT knockdown and overexpression on cellular behaviour. We also studied methyltransferase-like 3-mediated N6-methyladenosine modification in TERT transcripts and its influence on mRNA stability and cellular functions. Current results show that TERT expression is increased in EC tissue compared to both EU and NC. Knockdown of TERT inhibited the proliferation and migration of HESCs, while overexpression of TERT promoted these processes. We found a significant m^6A modification in TERT transcripts, especially in the 3' untranslated region (3'UTR); however, EC tissues had lower m^6A levels because METTL3 was downregulated. Mechanistically, m^6A modification by METTL3 negatively regulates TERT mRNA stability in a YTH N^6-methyladenosine RNA-binding protein 2 (YTHDF2)-dependent manner. Furthermore, METTL3 was found to negatively regulate the proliferation and migration of HESCs by promoting the decay of TERT transcripts. Together, our study identified a new molecular mechanism that underlies the pathogenesis of endometriosis. Inhibition of m^6A modification and the disruption of the METTL3/YTHDF2/TERT axis enhance cellular proliferation and migration, thereby contributing to the progression of endometriosis. These findings highlight potential targets for novel therapeutic strategies.