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.