title: SIN3A, generally regarded as a transcriptional repressor, is required for induction of gene transcription by the aryl hydrocarbon receptor.
abstract: CYP1A1 bioactivates several procarcinogens and detoxifies several xenobiotic compounds. Transcription of CYP1A1 is highly induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) via the aryl hydrocarbon receptor. We recently described an RNAi high throughput screening performed in the Hepa-1 mouse hepatoma cell line, which revealed that SIN3A is necessary for the induction of CYP1A1-dependent ethoxyresorufin-o-deethylase (EROD) enzymatic activity by TCDD. In the current studies, we sought to provide insight into the role of SIN3A in this process, particularly because studies on SIN3A have usually focused on its repressive activity on transcription. We report that ectopic expression of human SIN3A in Hepa-1 cells enhanced EROD induction by TCDD and efficiently rescued TCDD induction of EROD activity in cells treated with an siRNA to mouse SIN3A, thus validating a role for SIN3A in CYP1A1 induction. We demonstrate that SIN3A is required for TCDD induction of the CYP1A1 protein in Hepa-1 cells but not for expression of the aryl hydrocarbon receptor protein. In addition, siRNAs for SIN3A decreased TCDD-mediated induction of CYP1A1 mRNA and EROD activity in human hepatoma cell line Hep3B. We establish that TCDD treatment of Hepa-1 cells rapidly increases the degree of SIN3A binding to both the proximal promoter and enhancer of the Cyp1a1 gene and demonstrate that increased binding to the promoter also occurs in human Hep3B, HepG2, and MCF-7 cells. These studies establish that SIN3A physically interacts with the CYP1A1 gene and extends the transcriptional role of SIN3A to a gene that is very rapidly and dramatically induced.
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Molecular Toxicology Interdepartmental Program, and the Jonsson Comprehensive Cancer Center and.
authors.forename: Parrisa
authors.initials: P
authors.lastname: Solaimani
authors.affiliation: the Department of Chemistry and Biochemistry, UCLA, Los Angeles, California 90095.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Molecular Toxicology Interdepartmental Program, and the Jonsson Comprehensive Cancer Center and ohank@mednet.ucla.edu.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hankinson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D013723:Teratogens / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D013723:Teratogens; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: Aryl Hydrocarbon Receptor (AHR); Chromatin Immunoprecipitation (ChIP); Gene Transcription; Transcriptional Coactivator; Xenobiotic