Repression of FBXW7 by HES5 contributes to inactivation of the TGF-β signaling pathway and alleviation of endometriosis

Li-Juan Chen, Chen LJ, Lijuan Chen, Hu B, Bin Hu, Han ZQ, Zhi-Qiang Han, Zhiqiang Han, Liu W, Wei Liu, Jian-Hua Zhu, Zhu JH, Jianhua Zhu, Chen XX, Xuexing Chen, Xue-Xing Chen, Ziping Li, Zi-Ping Li, Li ZP, Zhou H, Hao Zhou
FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021 · vol. 35(2) , pp. e20938 · doi:10.1096/fj.202000438rrr · PMID:33496006 · W3122534423
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HES5 represses FBXW7 transcription and TGIF1 degradation, inactivating the TGF-β pathway and inhibiting endometrial stromal cell proliferation, invasion, and apoptosis, thereby alleviating endometriosis in mice.

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Abstract

Endometriosis (EMS) is a gynecologic disorder associated with infertility and characterized by the endometrial-type mucosa outside the uterine cavity. Currently available treatment modalities are limited to undesirable effects. Thus, in the present study, we sought to study the pathogenesis mechanism of EMS. For this purpose, the ectopic and eutopic endometrial tissues were resected from 86 patients with EMS and 54 infertile patients without EMS, respectively. The regulatory mechanism among HES family bHLH transcription factor 5 (HES5), transforming growth factor-beta (TGF-β)-induced factor 1 (TGIF1), F-box, and WD repeat domain containing 7 (FBXW7) was studied by performing co-immunoprecipitation, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, respectively. A mouse model of EMS was established to verify the aforementioned regulatory mechanism in vivo. Upregulation of HES5 and TGIF1, as well as downregulation of FBXW7, was observed in EMS endometrial tissues and human endometrial stromal cells (hESCs), respectively. The overexpression of HES5 was found to suppress the FBXW7 transcription and TGIF1 degradation, resulting in the inactivation of the TGF-β signaling pathway, as well as inhibition of hESC proliferation and invasion, thereby enhancing apoptosis. Results from a mouse model of EMS showed that the presence of HES5 contributed to the alleviation of EMS. Collectively, we attempted to provide a mechanistic insight into the unrecognized roles of the HES5/FBXW7 in EMS progression.

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Condition tags

endometriosisinfertility

MeSH descriptors

Basic Helix-Loop-Helix Proteins Endometriosis F-Box-WD Repeat-Containing Protein 7 Infertility, Female Repressor Proteins Signal Transduction Transforming Growth Factor beta Adult Adult Animals Animals Basic Helix-Loop-Helix Proteins Basic Helix-Loop-Helix Proteins Basic Helix-Loop-Helix Proteins Disease Models, Animal Disease Models, Animal Disease Progression Disease Progression Endometriosis Endometriosis

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