The EZH2-H3K27me3 axis modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury

Yingyan Chen; Leilei Ai; Yingyi Zhang; Xiang Li; Shiqian Xu; Weijie Yang; Jiamin Jin; Yerong Ma; Zhanhong Hu; Yinli Zhang; Yan Rong; Songying Zhang

doi:10.1038/s41420-023-01705-6

The EZH2-H3K27me3 axis modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury

Cell Death Discov. 2023 Nov 14;9(1):413. doi: 10.1038/s41420-023-01705-6.

Authors

Yingyan Chen^{1

2}, Leilei Ai^{1

2}, Yingyi Zhang^{1

2}, Xiang Li^{1

2}, Shiqian Xu^{1

2}, Weijie Yang^{1

2}, Jiamin Jin^{1

2}, Yerong Ma^{1

2}, Zhanhong Hu^{1

2}, Yinli Zhang^{1

2}, Yan Rong^{3

4}, Songying Zhang^{5

6}

Affiliations

¹ Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
² Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China.
³ Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. rongyan2015@zju.edu.cn.
⁴ Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China. rongyan2015@zju.edu.cn.
⁵ Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. zhangsongying@zju.edu.cn.
⁶ Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, China. zhangsongying@zju.edu.cn.

Abstract

Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer; however, the underlying mechanisms are still not fully understood. Our study has revealed a close association between epigenetic regulation and cyclophosphamide (CTX)-induced ovarian damage. Specifically, CTX and its active metabolite 4-hydroperoxy cyclophosphamide (4-HC) were found to increase the apoptosis of granulosa cells (GCs) by reducing EZH2 and H3K27me3 levels, both in vivo and in vitro. Furthermore, RNA-seq and CUT&Tag analyses revealed that the loss of H3K27me3 peaks on promoters led to the overactivation of genes associated with transcriptional regulation and apoptosis, indicating that stable H3K27me3 status could help to provide a safeguard against CTX-induced ovarian damage. Administration of the H3K27me3-demethylase inhibitor, GSK-J4, prior to CTX treatment could partially mitigate GC apoptosis by reversing the reduction of H3K27me3 and the aberrant upregulation of specific genes involved in transcriptional regulation and apoptosis. GSK-J4 could thus potentially be a protective agent for female fertility when undergoing chemotherapy. The results provide new insights into the mechanisms for chemotherapy injury and future clinical interventions for fertility preservation.