FOXA1 is essential for aryl hydrocarbon receptor-dependent regulation of cyclin G2
| Autor: | Sarra Al-Saigh, Shaimaa Ahmed, Jason Matthews |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Hepatocyte Nuclear Factor 3-alpha
Cancer Research Polychlorinated Dibenzodioxins Response element Cyclin G2 Estrogen receptor Breast Neoplasms Biology Nuclear Receptor Coactivator 3 Cell Line Tumor Humans RNA Small Interfering Molecular Biology Transcription factor Gene knockdown Binding Sites Estrogen Receptor alpha respiratory system Aryl hydrocarbon receptor Gene Expression Regulation Neoplastic Oncology Receptors Aryl Hydrocarbon Cancer cell Mutation Cancer research biology.protein Female FOXA1 Chromatin immunoprecipitation Signal Transduction |
| Zdroj: | Molecular cancer research : MCR. 10(5) |
| ISSN: | 1557-3125 |
| Popis: | 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. Mol Cancer Res; 10(5); 636–48. ©2012 AACR. |
| Databáze: | OpenAIRE |
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