Dimethylcelecoxib induces an inhibitory complex consisting of HDAC1/NF-κB(p65) RelA leading to transcriptional downregulation of mPGES-1 and EGR1
Dimethylcelecoxib induces an inhibitory complex consisting of HDAC1/NF-κB(p65) RelA leading to transcriptional downregulation of mPGES-1 and EGR1
复制标题
DOI：
10.1016/j.cellsig.2011.09.025
复制
发表时间：
2012-02-01
影响因子：
4.8
通讯作者：
Groesch, Sabine
中科院分区：
文献类型：
--
作者：
Deckmann, Klaus;Roersch, Florian;Groesch, Sabine
二甲基塞来昔布是塞来昔布的非COX-2抑制衍生物，通过转录抑制mPGES-1抑制PGE（2）合成。以前我们证明DMC下调EGFR 1表达并增加人宫颈癌细胞（HeLa）中的核NF-κ B [1]。这两种转录因子都是mPGES-1表达的重要调节因子。在这里，我们表明，用DMC处理HeLa细胞通过影响NF-κ B的反式激活活性来抑制EGFR 1启动子活性。使用siRNA突变NF-κ B基序以及下调NF-κ B（p65）RelA，可消除DMC对EGR 1启动子的抑制作用。NF-κ B的反式激活活性受多种共激活因子或共抑制因子的调节。其中一种共阻遏物是HDAC 1。DMC不影响HDAC 1的表达，但在DMC影响下HDAC活性增强。DMC处理后，NF-κ B与HDAC 1共免疫沉淀。电迁移率变化分析显示NF-κ B-HDAC 1和含有NF-κ B结合基序的DNA之间的相互作用增加。通过芯片检测，我们最终证实了NF-κ B和HDAC 1在EGFR 1启动子处的相互作用，该相互作用被HDAC 1抑制剂阿司他汀A部分逆转。使用针对HDAC 1的siRNA，我们可以消除DMC对EGR 1启动子的抑制作用。总之，我们证明了用DMC处理HeLa细胞导致由NF-κ B和HDAC 1组成的复合物的形成增强，所述复合物结合EGFR 1启动子，导致EGFR 1表达下调，其在mGPES-1表达的转录抑制中起主要作用。DMC的这些作用如何可能有助于各种疾病的潜在治疗益处进行了讨论。(C)2011 Elsevier Inc. All rights reserved.
Dimethylcelecoxib, a non-COX-2 inhibiting derivative of celecoxib, inhibits PGE(2) synthesis by transcriptional inhibition of mPGES-1. Previously we demonstrated that DMC downregulates EGR1 expression and increases nuclear NF-kappa B in human cervical cancer cells (HeLa) [1]. Both transcription factors are important regulators of mPGES-1 expression. Here we show that treatment of HeLa cells with DMC inhibits EGR1 promoter activity by influencing the transactivation activity of NF-kappa B. Mutation of the NF-kappa B motif as well as downregulation of NF-kappa B(p65)RelA using siRNA repealed the inhibitory effect of DMC on the EGR1 promoter. The transactivation activity of NF-kappa B is regulated by various co-activators or co-repressors. One of these co-repressors is HDAC1. DMC did not influence HDAC1 expression, but the HDAC activity was enhanced under DMC influence. After DMC treatment NF-kappa B co-immunoprecipitated with HDAC1. Electromobility shift assays depicted an increased interaction between NF-kappa B-HDAC1 and DNA containing NF-kappa B binding motives. Performing CHIP-assays we finally demonstrated the interaction of NF-kappa B and HDAC1 at the EGR1 promoter that was in part reversed by the HDAC1 inhibitor trichostatin A. Using siRNA against HDAC1 we could repeal the inhibitory effect of DMC on the EGR1 promoter. In conclusion we demonstrated that treatment of HeLa cells with DMC leads to an enhanced formation of a complex consisting of NF-kappa B and HDAC1 that binds to the EGR1 promoter resulting in downregulation of EGR1 expression which plays a major role for transcriptional inhibition of mGPES-1 expression. How these effects of DMC may contribute to a potential therapeutical benefit of various diseases is discussed. (C) 2011 Elsevier Inc. All rights reserved.