title: Dimethylcelecoxib induces an inhibitory complex consisting of HDAC1/NF-κB(p65)RelA leading to transcriptional downregulation of mPGES-1 and EGR1.
abstract: 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-κB in human cervical cancer cells (HeLa). 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-κB. Mutation of the NF-κB motif as well as downregulation of NF-κB(p65)RelA using siRNA repealed the inhibitory effect of DMC on the EGR1 promoter. The transactivation activity of NF-κB 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-κB co-immunoprecipitated with HDAC1. Electromobility shift assays depicted an increased interaction between NF-κB-HDAC1 and DNA containing NF-κB binding motives. Performing CHIP-assays we finally demonstrated the interaction of NF-κB 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-κB 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.
authors: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany.
authors: Klaus
authors: K
authors: Deckmann
authors: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany.
authors: Florian
authors: F
authors: Rörsch
authors: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany.
authors: Gerd
authors: G
authors: Geisslinger
authors: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt/Main, Germany. Electronic address: groesch@em.uni-frankfurt.de.
authors: Sabine
authors: S
authors: Grösch
mesh_terms: D000068579:Celecoxib; D015232:Dinoprostone / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006367:HeLa Cells; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D047468:Immunoprecipitation; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051996:Transcription Factor RelA; C012589:trichostatin A; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000068579:Celecoxib; D015232:Dinoprostone