Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Baoshan Branch, Shanghai, 201900, China.
Biomed Pharmacother. 2019 May;113:108712. doi: 10.1016/j.biopha.2019.108712. Epub 2019 Mar 6.
Progestins has been used widely for endometrial cancer (EC) patients. However, long term use of high dose progestin often lead to progestin resistance. Our previous studies have demonstrated that metformin reversed progestin resistance through the downregulation of the expression of glyoxalase I (GLOI) in type I endometrial cancer. Recent studies have demonstrated the role of Ten-eleven translocation 1 (TET1) in endometrial cancer, but the physiological role of TET1 in GLOI-mediated progestin resistance has been poorly addressed. Immunohistochemistry was used to detect the expression of TET1, GLOI and 5hmC in various endometrium. Western blot was carried out to analyses TET1 and GLOI expression with different treatment. Cell counting kit-8 was used to evaluate cell proliferation after various treatment. Dot blot assay and HMeDIP assay were performed to detect global hydroxmethylation levels and hydroxymethylation levels in GLOI gene respectively. In current study, we found that metformin effectively sensitized progestin in endometrial cancer cell lines through the down regulation of the expression of TET1 and GLOI. Interestingly, the exogenous increase of TET1 expression enhanced total 5hmC level and hydroxymethylation modification in glyoxalase I promoter region. This effect was abated by metformin treatment. Moreover, the expression profile of TET1 and glyoxalase I in various endometrial tissue parallelized with 5hmC level. Therefore, this finding suggests that metformin sensitized progestin in endometrial cancer through the TET1-5hmC-GLOI signaling pathway.
孕激素被广泛用于子宫内膜癌（EC）患者。然而，长期大剂量使用孕激素往往会导致孕激素耐药。我们之前的研究表明，二甲双胍通过下调 I 型子宫内膜癌中糖氧还蛋白 I（GLOI）的表达来逆转孕激素耐药。最近的研究表明，Ten-eleven 易位酶 1（TET1）在子宫内膜癌中发挥作用，但 TET1 在 GLOI 介导的孕激素耐药中的生理作用尚未得到充分阐明。免疫组织化学用于检测各种子宫内膜中 TET1、GLOI 和 5hmC 的表达。Western blot 用于分析不同处理下 TET1 和 GLOI 的表达。细胞计数试剂盒-8 用于评估各种处理后的细胞增殖。点印迹分析和 HMeDIP 分析分别用于检测全局羟甲基化水平和 GLOI 基因中的羟甲基化水平。在本研究中，我们发现二甲双胍通过下调 TET1 和 GLOI 的表达，有效地使孕激素在子宫内膜癌细胞系中敏感。有趣的是，外源性增加 TET1 的表达增强了糖氧还蛋白 I 启动子区域的总 5hmC 水平和羟甲基化修饰。二甲双胍处理可减弱这种效应。此外，各种子宫内膜组织中 TET1 和糖氧还蛋白 I 的表达谱与 5hmC 水平平行。因此，这一发现表明，二甲双胍通过 TET1-5hmC-GLOI 信号通路使孕激素在子宫内膜癌中敏感。
