Hyperandrogen enhances apoptosis of human ovarian granulosa cells via up-regulation and demethylation of PDCD4

Abstract

Apoptosis of granulosa cells (GCs) induced by hyperandrogen plays a key role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the mechanism of androgen-induced apoptosis of GCs has not been clarified to date. Recent studies have reported that PDCD4 expression is higher in PCOS patients and might be a key factor in PCOS progression. In this study, we aimed to investigate the role of PDCD4 in regulating apoptosis of human GCs and whether hyperandrogen regulate PDCD4 expression through DNA methylation. Overexpression of PDCD4 in human ovarian granulosa cell line KGN cells promoted cells apoptosis. Meanwhile, expression of caspase-3 and caspase-9 were significantly elevated. High concentration of testosterone treatment resulted in up-regulation of PDCD4 and a significant increase of apoptosis in KGN cells. In addition, knockdown of PDCD4 in KGN cells treated with high concentration of testosterone abolished the hyperandrogen-induced apoptosis. Furthermore, high concentration of testosterone down-regulated DNMT1, DNMT3A and DNMT3B expression and the methylation level in the promoter region of PDCD4 was decreased. In conclusion, PDCD4 can promote apoptosis of human ovarian GCs. The mechanism of hyperandrogen-induced apoptosis may be mediated by PDCD4. Furthermore, the up-regulation of PDCD4 induced by hyperandrogen may through demethylation of its promoter regions.