Sun H Sunny, Hsiao Kuei-Yang, Hsu Chih-Chao, Wu Meng-Hsing, Tsai Shaw-Jenq
Institute of Molecular Medicine, National Cheng Kung University Medical College, Tainan 70101, Taiwan, Republic of China.
Endocrinology. 2003 Sep;144(9):3934-42. doi: 10.1210/en.2003-0289.
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.
类固醇生成急性调节蛋白（StAR）调节类固醇生物合成的首个关键步骤，因此，子宫内膜异位植入物中StAR的异常表达在子宫内膜异位症的病因学中起关键作用。然而，异位子宫内膜组织中StAR异常表达的机制仍不清楚。在本研究中，我们证明前列腺素（PG）E2在细胞和分子水平上刺激StAR蛋白表达。PGE2导致StAR表达迅速增加，这涉及EP2受体偶联蛋白激酶A途径的激活。EP2受体激活诱导细胞外信号调节激酶（ERK）和环磷酸腺苷反应元件结合蛋白（CREB）磷酸化。然而，ERK的激活不参与CREB磷酸化或StAR表达。PGE2诱导的CREB磷酸化增加了CREB结合蛋白的募集，从而增加了组蛋白H3乙酰化。染色质免疫沉淀实验表明，用PGE2处理30分钟后，与StAR启动子近端区域结合的乙酰化组蛋白H3增加，同时新生StAR RNA转录也增加。用组蛋白脱乙酰酶抑制剂曲古抑菌素A处理可增强PGE2诱导的新生StAR RNA转录。我们得出结论，涉及EP2受体、蛋白激酶A、CREB和CREB结合蛋白的组蛋白H3乙酰化增加是PGE2诱导子宫内膜异位基质细胞中StAR基因激活的原因。我们目前的报告可能为理解雌激素异常局部产生的机制和子宫内膜异位症的病因提供新的见解。
