Transactivation of Steroidogenic Acute Regulatory Protein in Human Endometriotic Stromal Cells Is Mediated by the Prostaglandin EP2 Receptor
Open Access
- 1 September 2003
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 144 (9) , 3934-3942
- https://doi.org/10.1210/en.2003-0289
Abstract
Steroidogenic acute regulatory protein (StAR) regulates the first committed step in the biosynthesis of steroids, and thus aberrant expression of StAR in endometriotic implants plays a critical role in the etiology of endometriosis. However, the mechanism responsible for abnormal expression of StAR in ectopic endometriotic tissues remains unknown. In the present study, we demonstrate that prostaglandin (PG) E2 stimulates StAR protein expression at the cellular and molecular levels. PGE2 caused a rapid increase in StAR expression that involves activation of the EP2 receptor-coupled protein kinase A pathway. Activation of EP2 receptor-induced phosphorylation of ERK and cAMP response element binding protein (CREB). However, activation of ERK did not involve in CREB phosphorylation or concomitantly StAR expression. Phosphorylation of CREB induced by PGE2 increased the recruitment of CREB binding protein and thus histone H3 acetylation. Chromatin immunoprecipitation experiments showed that acetylated histone H3 bound to the proximal region of the StAR promoter was increased after 30 min treatment with PGE2, and this was mirrored by an increase in nascent StAR RNA transcription. Treatment with the histone deacetylase inhibitor, tricostatin A, enhanced PGE2-induced nascent StAR RNA transcription. We conclude that increased histone H3 acetylation involving the EP2 receptor, protein kinase A, CREB, and CREB binding protein is responsible for PGE2-induced StAR gene activation in endometriotic stromal cells. Our current report may provide new insights in understanding mechanism of abnormally local production of estrogen and the etiology of endometriosis.Keywords
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