Transactivation of Steroidogenic Acute Regulatory Protein in Human Endometriotic Stromal Cells Is Mediated by the Prostaglandin EP2 Receptor

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) E(2) stimulates StAR protein expression at the cellular and molecular levels. PGE(2) 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 PGE(2) 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 PGE(2), and this was mirrored by an increase in nascent StAR RNA transcription. Treatment with the histone deacetylase inhibitor, tricostatin A, enhanced PGE(2)-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 PGE(2)-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.

Prostaglandin E2-EP4 Receptor Promotes Endothelial Cell Migration via ERK Activation and Angiogenesis in Vivo

“…In contrast, activation of EP2 by Butaprost has been shown to promote both PKA and ERK activation in human endometriotic stromal cells (24). Thus the ability of the EP2 receptor to promote ERK activation is dependent on the dose of the ligand(s) as well as the cell type.…”

Regulation of Aromatase Expression in Estrogen-Responsive Breast and Uterine Disease: From Bench to Treatment

“…Research work from our laboratory and other investigators over the past 10 years uncovered a molecular link between inflammation and estrogen production in endometriosis ). This is mediated by a positive-feedback cycle that favors expression of key steroidogenic genes, most notably StAR and aromatase, expression of COX-2, and continuous local production of estradiol and PGE 2 in endometriotic tissue Tsai et al, 2001;Sun et al, 2003) (Fig. 11).…”

Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

“…Clone 4 of SK-N-SH cells stably expressing Egr-1 was mock transfected or transfected with the ICP27 or mutated ICP27 promoter plasmid. At 48 hours after transfection, these transfectants were subjected to ChIP assay using the method previously described (41,42), with modifications. In brief, the chromatins were immunoprecipitated by anti-Egr-1 antibody or rabbit IgG (Santa Cruz Biotechnology Inc.).…”