Metformin Sensitizes Endometrial Cancer Cells To Progestin By Targeting TET1 To Downregulate Glyoxalase ? Expression

Objective: Progestin has been widely used for endometrial cancer(EC)patients.However,long term use of high dose progestin often leads to progestin resistance.Our previous study documented that metformin is capable of reversing progestin resistance by downregulating glyoxalase I(GLOI)expression in type I endometrial cancer,but the underlying mechanism is unrevealed.Recent finding stated Ten-eleven translocation 1(TET1)involves in endometrial cancer occurrence,whether it plays a role in GLOI-mediated progestin resistance is not clear.This study aimed to evaluate the profile of TET1 in GLOI-mediated metformin enhancing progestin sensitivity in endometrial cancer.Methods: Immunohistochemistry was used to detect the expression of TET1,GLOI and 5hm C in various endometrium.Western blot was carried out to analyse TET1 and GLOI expression with different treatment.Cell counting kit-8 was used to evaluate cell proliferation after various treatments.Dot blot assay and HMe DIP assay were performed to detect global hydroxymethylation levels and hydroxymethylation levels in GLOI gene respectively.Results: In current study,we found that metformin partly induced cell death and effectively sensitized progestin in endometrial cancer cell lines.The exogenous increase of TET1 expression enhanced total 5hm C level and hydroxymethylation modification in GLOI promoter region.These effects could be ablated by addition of metformin.Meanwhile,the expression profile of TET1 and GLOI in gradually varied endometrial pathological status parallelized with 5hm C level.Conclusions: These findings suggest that metformin suppresses TET1 expression to inhibit hydroxymethylation in GLOI,which is a key mechanism of enhancing progestin sensitivity in endometrial cancer.