USP25 Regulates the Proliferation and Apoptosis of Ovarian Granulosa Cells In Polycystic Ovary Syndrome by Modulating the PI3K/AKT Pathway via Deubiquitinating PTEN

Background: Polycystic ovarian syndrome (PCOS) is an endocrine-related disease related to abnormal folliculogenesis and is a leading cause of infertility worldwide. Inhibition of granulosa cells (GCs) proliferation and increased GCs apoptosis have been identified as the major factors in aberrant follicle maturation. Methods: USP25 and PTEN expression in GCs from women with and without PCOS was analyzed using Western blotting. A PCOS-like mouse model was constructed using USP25 knockout and wild-type mice to explore the role of USP25 in PCOS. The human granular cell line KGN was cultured for proliferation and apoptosis assays, and the effect of USP25 on PTEN was investigated after transfection with shRNA-USP25 lentivirus. Findings: USP25 expression was found to be elevated in patients and mice with PCOS. With mouse model, we observed a reduction in PCOS symptoms in mice after USP25 deletion. Increased proliferation, reduced apoptosis, activation of the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and decreased PTEN expression were found in KGN cells after USP25 knockdown. Finally, we verified that USP25 could deubiquitinate PTEN in KGN cells. Interpretation: In this study, we investigated that USP25 can regulate the PI3K/AKT signaling pathway by deubiquitinating PTEN, thus affecting the proliferation and apoptosis of GCs and contributing to the pathogenesis of PCOS. Funding Information: This work was supported by the National Key Research and Development Program of China (grant nos. 2018YFC1002804 and 2016YFC1000600) and the National Natural Science Foundation of China (grant nos. 81771618, 81971356 and 82101749). Declaration of Interests: The authors declare that there is no conflict of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of Renmin Hospital of Wuhan University. Signed informed consent was received from all subjects (No. WDRY2019-K077). The procedures for animal experiments were performed following the Guide for the Care and Use of the Animal Experiment Center Renmin Hospital of Wuhan University, and the approval ID for the animal experiment was WDRM20191203.