Dimethylcelecoxib induces an inhibitory complex consisting of HDAC1/NF-¦ÊB(p65)RelA leading to transcriptional downregulation of mPGES-1 and EGR1

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• 作者：Klaus  ; Deckmann^a ; Florian  ; Rö ; rsch^a ; Gerd  ; Geisslinger^a ; Sabine  ; Grö ; sch ;   ; ^a ;   ; ^{groesch@em.uni-frankfurt.de}
• 关键词：Dimethylcelecoxib ; mPGES-1 ; COX-inhibitor ; EGR1 ; NF-¦ÊB ; RelA ; HDAC1
• 刊名：Cellular Signalling
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：24
• 期：2
• 页码：460-467
• 全文大小：1019 K

文摘

Dimethylcelecoxib, a non-COX-2 inhibiting derivative of celecoxib, inhibits PGE₂ synthesis by transcriptional inhibition of mPGES-1. Previously we demonstrated that DMC downregulates EGR1 expression and increases nuclear NF-¦ÊB 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-¦ÊB. Mutation of the NF-¦ÊB motif as well as downregulation of NF-¦ÊB(p65)RelA using siRNA repealed the inhibitory effect of DMC on the EGR1 promoter. The transactivation activity of NF-¦ÊB 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-¦ÊB co-immunoprecipitated with HDAC1. Electromobility shift assays depicted an increased interaction between NF-¦ÊB¨CHDAC1 and DNA containing NF-¦ÊB binding motives. Performing CHIP-assays we finally demonstrated the interaction of NF-¦ÊB 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-¦ÊB 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.