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.
Yamaguchi
Kentaro
K
Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA.
Lantowski
Agnieszka
A
Dannenberg
Andrew J
AJ
Subbaramaiah
Kotha
K
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