Chabane Nadir, Li Xinfang, Fahmi Hassan
Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Department of Medicine, Notre-Dame Hospital, University of Montreal, 1560 Sherbrooke Street East, Montreal, Quebec, Canada H2L 4M1.
J Cell Biochem. 2009 Feb 15;106(3):453-63. doi: 10.1002/jcb.22027.
Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2), which contributes to many physiopathological processes. We show here that inhibitors of histone deacetylase (HDAC) activity, trichostatin A (TSA), butyric acid (BA), and valproic acid (BA) prevented IL-1-induced mPGES-1 protein expression in human synovial fibroblasts. TSA also inhibited IL-1-induced mPGES-1 mRNA expression and promoter activation. Overexpression of HDAC4, but not of HDAC1, 2, 3, 5, or 6 enhanced, whereas HDAC4 silencing with small interfering RNA (siRNA) reduced, IL-1-induced mPGES-1 promoter activation, implying that HDAC4 contributes to mPGES-1 gene expression. Consistently, IL-1-induced mPGES-1 protein expression was prevented by siRNA for HDAC4. We also demonstrate that IL-1-induced HDAC4 recruitment to the mPGES-1 promoter. This recruitment was not accompanied by deacetylation of histones H3 and H4, suggesting that HDAC4 contributes to mPGES-1 induction independently of local deacetylation of histones H3 and H4. We then investigated whether HDAC4 regulates mPGES-1 expression by modulating the activity of Egr-1, a key transcription factor in IL-1-induced mPGES-1 expression. We found that HDAC4 overexpression enhances, whereas HDAC4 knockdown by siRNA reduces Egr-1-mediated activation of the mPGES-1 promoter. Together these data indicate that HDAC4 contributes to transcriptional induction of mPGES-1 by IL-1 through a mechanism involving up-regulation of Egr-1 transcriptional activity.
微粒体前列腺素E合酶-1（mPGES-1）催化前列腺素E2（PGE2）生物合成的最后一步，PGE2参与许多生理病理过程。我们在此表明，组蛋白脱乙酰酶（HDAC）活性抑制剂曲古抑菌素A（TSA）、丁酸（BA）和丙戊酸（VPA）可阻止白细胞介素-1（IL-1）诱导人滑膜成纤维细胞中mPGES-1蛋白表达。TSA还抑制IL-1诱导的mPGES-1 mRNA表达和启动子激活。过表达HDAC4（而非HDAC1、2、3、5或6）可增强IL-1诱导的mPGES-1启动子激活，而用小干扰RNA（siRNA）沉默HDAC4则可降低该激活，这意味着HDAC4参与mPGES-1基因表达。同样，针对HDAC4的siRNA可阻止IL-1诱导的mPGES-1蛋白表达。我们还证明，IL-1可诱导HDAC4募集至mPGES-1启动子。这种募集并未伴随组蛋白H3和H4的去乙酰化，表明HDAC4独立于组蛋白H3和H4的局部去乙酰化作用参与mPGES-1的诱导。然后，我们研究了HDAC4是否通过调节早期生长反应因子-1（Egr-1）的活性来调节mPGES-1表达，Egr-1是IL-1诱导mPGES-1表达中的关键转录因子。我们发现，HDAC4过表达可增强，而siRNA介导的HDAC4敲低可降低Egr-1介导的mPGES-1启动子激活。这些数据共同表明，HDAC4通过涉及上调Egr-1转录活性的机制参与IL-1对mPGES-1的转录诱导。
