Testosterone-Induced H3K27 Deacetylation Participates in Granulosa Cell Proliferation Suppression and Pathogenesis of Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is the leading cause of infertility in reproductive-age women. Hyperandrogenism, polycystic ovaries, and chronic anovulation are its typical clinical features. However, the correlation between hyperandrogenism and ovarian follicle growth aberrations remains poorly understood. To advance our understanding of the molecular alterations in ovarian granulosa cells (GCs) with excessive androgen, epigenetic changes and affected gene expression in human granulosa-lutein cells and immortalized human GCs were evaluated. A PCOS mouse model induced by dihydrotestosterone was also established. This study found that excessive testosterone significantly decreased the acetylation of lysine 27 on histone H3 (H3K27Ac). H3K27Ac chromatin immunoprecipitation-sequencing data showed down-regulated expression of cell cycle-related genes CCND1, CCND3, and PCNA, which was confirmed by real-time quantitative PCR and Western blot analysis. Testosterone application impeding cell proliferation was also shown by Ki-67 immunofluorescence and flow-cytometric analysis. Moreover, testosterone influenced casein kinase 2 alpha (CK2α) nuclear translocation, which increased the phosphorylation level of histone deacetylase 2 (HDAC2). Inhibition of CK2α nuclear translocation or silenced HDAC2 expression efficiently retarded H3K27 acetylation. PCOS mouse model experiments also demonstrated decreased H3K27Ac and enhanced HDAC2 phosphorylation in GCs. Cell proliferation-related genes were also down-regulated in PCOS mouse GCs. In conclusion, hyperandrogenism in human and mouse GCs caused H3K27Ac aberrations, which are associated with CK2α nuclear translocation and HDAC2 phosphorylation, participating in abnormal follicle development in patients with PCOS.