Metformin sensitizes endometrial cancer cells to progestin by targeting TET1 to downregulate glyoxalase I expression

Yanyu Jiang; Xiong Chen; Youheng Wei; Youji Feng; Wenxin Zheng; Zhenbo Zhang

Biomedicine & Pharmacotherapy (May 2019)

Metformin sensitizes endometrial cancer cells to progestin by targeting TET1 to downregulate glyoxalase I expression

Yanyu Jiang,
Xiong Chen,
Youheng Wei,
Youji Feng,
Wenxin Zheng,
Zhenbo Zhang

Affiliations

Yanyu Jiang: Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
Xiong Chen: Department of Obstetrics and Gynecology, Shanghai First People’s Hospital, Baoshan Branch, Shanghai, 201900, China
Youheng Wei: Institute of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
Youji Feng: Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
Wenxin Zheng: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Zhenbo Zhang: 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; Corresponding author at: Reproductive Medicine Center, Shanghai General Hospital, Shanghai Jiaotong University, 100 Haining Road, Shanghai 200080, China.

Journal volume & issue: Vol. 113

Abstract

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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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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