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01-12-2014 | Original Article

PGE2 modulates the transcriptional activity of ERRa in prostate stromal cells

Authors: Zhaochen Ning, Xiaoling Du, Ju Zhang, Kuo Yang, Lin Miao, Yan Zhu, Hui Yuan, Linlin Wang, Helmut Klocker, Jiandang Shi

Published in: Endocrine | Issue 3/2014

Abstract

The regulation of the transcriptional activity of the estrogen receptor-related receptor a (ERRa) has not yet been clearly documented. Aromatase is a direct target gene of ERRa, and we previously reported that prostaglandin E2 (PGE2) increased the expression of ERRa in the prostate stromal cell line WPMY-1, which ultimately promoted estradiol production by enhancing aromatase gene transcription. Here, we show that PGE2 also affects aromatase expression by regulating ERRa transcriptional activity in prostate stromal cells. When the cells were cultured in serum-free medium, the expression of aromatase was not proportional to the ERRa protein level, if no other stimulation occurred, indicating the absence of a factor that activates ERRa. PGE2 could upregulate aromatase and ERRa response element (ERRE)-reporter expression and also enhance ERRa phosphorylation and nuclear localization. PGE2 functions through the PGE2 receptors (EP) 2 and EP4, which couple to adenylate cyclase. The activation of adenylate cyclase with Forskolin mimicked the PGE2-mediated enhancement of extracellular signal-regulated kinase (ERK) phosphorylation and ERRa target gene expression. Experiments using specific signaling pathway inhibitors showed that both phosphatidylinositol 3-kinase (PI3K) and ERK are involved in ERRa activation, and the PI3K inhibitor was shown to abolish ERK activation. Our results suggest that PGE2 is a modulator of ERRa transcriptional activity. Furthermore, PGE2 activates the EP2/EP4-cAMP-PI3K-ERK signaling pathway, which enhanced ERRa transcriptional potentiality by increasing ERRa phosphorylation and nuclear translocation, subsequently promoting the expression of its target genes, such as aromatase.

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Title: PGE2 modulates the transcriptional activity of ERRa in prostate stromal cells
Authors: Zhaochen Ning
Xiaoling Du
Ju Zhang
Kuo Yang
Lin Miao
Yan Zhu
Hui Yuan
Linlin Wang
Helmut Klocker
Jiandang Shi
Publication date: 01-12-2014
Publisher: Springer US
Published in: Endocrine / Issue 3/2014
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-014-0261-7

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