title: FOXA1 is essential for aryl hydrocarbon receptor-dependent regulation of cyclin G2.
abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recently, AHR has emerged as a potential therapeutic target for breast cancer by virtue of its ability to modulate estrogen receptor-α (ERα) signalling and/or its ability to block cell proliferation. Our previous studies identified cyclin G2 (CCNG2), an inhibitor of cell-cycle progression, as an AHR target gene; however, the mechanism of this regulation is unknown. Chromatin immunoprecipitation assays in T-47D human breast cancer cells revealed a TCDD-dependent recruitment of AHR, nuclear co-activator 3 (NCoA3) and the transcription factor forkhead box A1 (FOXA1), a key regulator of breast cancer cell signaling, to CCNG2 resulting in increases in CCNG2 mRNA and protein levels. Mutation of the AHR response element (AHRE) and forkhead-binding sites abolished TCDD-induced CCNG2-regulated reporter gene activity. RNA interference-mediated knockdown of FOXA1 prevented the TCDD-dependent recruitment of AHR and NCoA3 to CCNG2 and reduced CCNG2 mRNA levels. Interestingly, knockdown of FOXA1 also caused a marked decrease in ERα, but not AHR protein levels. However, RNA interference-mediated knockdown of ERα, a negative regulator of CCNG2, had no effect on TCDD-dependent AHR or NCoA3 recruitment to or expression of CCNG2. These findings show that FOXA1, but not ERα, is essential for AHR-dependent regulation of CCNG2, assigning a role for FOXA1 in AHR action.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Medical Sciences Building, Room 4336, 1 King's College Circle, Toronto, Ontario, Canada, M5S 1A8.
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Ahmed
authors.forename: Sarra
authors.initials: S
authors.lastname: Al-Saigh
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
mesh_terms: D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D056767:Cyclin G2 / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D056767:Cyclin G2; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D000072317:Polychlorinated Dibenzodioxins; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3