Histone deacetylase inhibitors suppress the induction of c-Jun and its target genes including COX-2.
Cyclooxygenase-2 (COX-2) is considered to be a target for anticancer therapy. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP-1-mediated activation of COX-2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP-1-mediated induction of COX-2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c-Jun binding to the COX-2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c-Jun. HDAC inhibitors suppressed the induction of c-jun transcription by blocking the recruitment of the preinitiation complex (RNA polymerase II and TFIIB) to the c-jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP-1-mediated stimulation of c-jun expression. Because HDAC inhibitors suppressed the induction of c-jun gene expression, resulting in reduced COX-2 transcription, it was important to determine whether other known AP-1 target genes were also modulated. Cyclin D1 and collagenase-1 are AP-1-dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase-1 transcription by inhibiting the binding of c-Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c-jun transcription by inhibiting the recruitment of the preinitiation complex to the c-jun promoter. This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Kentaro
K
Yamaguchi
Agnieszka
A
Lantowski
Andrew J
AJ
Dannenberg
Kotha
K
Subbaramaiah
D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017364:Collagenases / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D016758:Genes, jun; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D035581:Transcription Factor TFIIB / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000077337:Vorinostat; D000099186:Histone Deacetylase 3
D002843:Chromatin; D017364:Collagenases; D019938:Cyclin D1; D015232:Dinoprostone; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D016755:Proto-Oncogene Proteins c-jun; D012319:RNA Polymerase II; D018808:Transcription Factor AP-1; D035581:Transcription Factor TFIIB; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; C012589:trichostatin A; C417249:collagenase 1