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-a (ERa) signalling and/or its ability to block cell proliferation. Our previous studies identified cyclin G2 (CCNG2), an inhibitor of cellcycle 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 ERa, but not AHR protein levels. However, RNA interference-mediated knockdown of ERa, 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 ERa, is essential for AHR-dependent regulation of CCNG2, assigning a role for FOXA1 in AHR action. Mol Cancer Res; 10(5); 636-48. Ó2012 AACR.

Estrogen receptor-α and aryl hydrocarbon receptor involvement in the actions of botanical estrogens in target cells

“…The cell-context dependence of gene regulation by nuclear receptors is well documented and is thought to be determined by differences in cell background, in particular by differences in the contents of coregulators and other cofactors with which these receptors bind to form multicomponent complexes that regulate gene expression at the chromatin level (Lonard and O’Malley, 2012; McKenna et al, 2014; Smith and O’Malley, 2004; Stender et al, 2010). In fact, it is noteworthy that ERα and AhR interact with many of the same coregulators and cofactors, including the coregulators RIP140 (Madak-Erdogan and Katzenellenbogen, 2012), SRC 1, 2, and 3 (Endler et al, 2012; Madak-Erdogan and Katzenellenbogen, 2012) and FOXA1 (Ahmed et al, 2012). …”

Cyclin G2: A novel independent prognostic marker in pancreatic cancer

“…Previous studies have reported that CCNG2 participates in carcinogenesis and is a known tumor suppressor gene (15)(16)(17)(20)(21)(22)(23)(24)(25)(26). CCNG2 gene expression is downregulated in thyroid (20), oral (21), ovarian (22), breast (23,24), gastric (16), esophageal (17), prostate (25), kidney (26) and colorectal (15) cancer cells.…”

Cohesin modulates transcription of estrogen-responsive genes

“…Baseline expression of a subset of genes (e.g., CCNG2, an inhibitor of cell cycle-progression [69]; Fig. S6) was altered by RAD21 depletion in the absence of estrogen, perhaps reflecting inhibition of entry into the cell cycle.…”