Estrogen Receptor-Related Receptor α Mediates Up-Regulation of Aromatase Expression by Prostaglandin E2 in Prostate Stromal Cells

Estrogen receptor-related receptor alpha (ERR alpha) is an orphan member of the nuclear receptor superfamily of transcription factors. ERR alpha is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERR alpha, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERR alpha, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERR alpha expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERR alpha activity by chlordane (an antagonist of ERR alpha) or small interfering RNA knockdown of ERR alpha blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERR alpha significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERR alpha directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERR alpha and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17 beta-Estradiol concentration in WPMY-1 medium was up-regulated by ERR alpha expression, and that was further increased by PGE2. Our results provided evidence that ERR alpha contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERR alpha in estrogen-related prostatic diseases. (Molecular Endocrinology 24: 1175-1186, 2010)