Effects of histone deacetylase inhibitors on the Ah receptor gene promoter.
The aromatic hydrocarbon receptor (AhR) is a ligand-dependent basic helix-loop-helix-PAS-containing transcription factor which is activated by chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Constitutive expression of the AhR gene occurs in a tissue- and developmentally specific manner and appears to be altered by chemicals which affect histone deacetylase (HDAC) activity in cells in culture. Here we have directly characterized the effects of two HDAC inhibitors, n-butyrate and trichostatin A, on the promoter activity of the murine AhR gene. HDAC inhibitors increased the constitutive activity of the AhR gene promoter in a luciferase reporter construct by five- to sevenfold in a dose- and time-dependent manner in several cell lines and was correlated with an increase in endogenous AhR activity in an AhR-deficient cell line. Deletion analysis of the upstream region of the AhR gene localized the HDAC inhibitor effect to a 167-bp region encompassing -77 to +90 of the AhR gene promoter. Cotransfection of an AhR promoter-luciferase reporter plasmid with a vector expressing the E1A(12s) oncoprotein, a negative regulator of p300, a protein with histone acetylase activity, decreased AhR promoter activity fivefold. Overall, our results support a role for histone acetylation in the transcriptional activity of the AhR gene promoter.
Garrison
P M
PM
Department of Environmental Toxicology, Meyer Hall, One Shields Avenue, Davis, California 95616, USA.
Rogers
J M
JM
Brackney
W R
WR
Denison
M S
MS
D000818:Animals; D001943:Breast Neoplasms; D002087:Butyrates / Q000494:pharmacology*; D019556:COS Cells; D006528:Carcinoma, Hepatocellular; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D017930:Genes, Reporter; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms; D008156:Luciferases / Q000235:genetics; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured
D002087:Butyrates; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018336:Receptors, Aryl Hydrocarbon; D019319:Okadaic Acid; C012589:trichostatin A; D008156:Luciferases