Resveratrol Prevents Epigenetic Silencing of BRCA-1 by the Aromatic Hydrocarbon Receptor in Human Breast Cancer Cells ,

Abstract

The BRCA-1 protein is a tumor suppressor involved in repair of DNA damage. Epigenetic mechanisms contribute to its reduced expression in sporadic breast tumors. Through diet, humans are exposed to a complex mixture of xenobiotics and natural ligands of the aromatic hydrocarbon receptor (AhR), which contributes to the etiology of various types of cancers. The AhR binds xenobiotics, endogenous ligands, and many natural dietary bioactive compounds, including the phytoalexin resveratrol (Res). In estrogen receptor- alpha (ER alpha )-positive and BRCA-1 wild-type MCF-7 breast cancer cells, we investigated the influence of AhR activation with the agonist 2,3,7,8 tetrachlorobenzo(p)dioxin (TCDD) on epigenetic regulation of the BRCA-1 gene and the preventative effects of Res. We report that activation and recruitment of the AhR to the BRCA-1 promoter hampers 17 beta -estradiol (E2)-dependent stimulation of BRCA-1 transcription and protein levels. These inhibitory effects are paralleled by reduced occupancy of ER alpha , acetylated histone (AcH)-4, and AcH3K9. Conversely, the treatment with TCDD increases the association of mono-methylated-H3K9, DNA-methyltransferase-1 (DNMT1), and methyl-binding domain protein-2 with the BRCA-1 promoter and stimulates the accumulation of DNA strand breaks. The AhR-dependent repression of BRCA-1 expression is reversed by small interference for the AhR and DNMT1 or pretreatment with Res, which reduces TCDD-induced DNA strand breaks. These results support the hypothesis that epigenetic silencing of the BRCA-1 gene by the AhR is preventable with Res and provide the molecular basis for the development of dietary strategies based on natural AhR antagonists.

Targeting the Epigenome with Bioactive Food Components for Cancer Prevention

“…DNA hypomethylation by curcumin (3 and 30 M ) in MV4-11 human leukemia cells was thought to involve the covalent blocking of the catalytic pocket of DNMT1 [63] . Resveratrol (10 and 20 M ) reversed epigenetic silencing of breast cancer 1 ( BRCA-1 ) by the aromatic hydrocarbon receptor agonist 2,3,7,8-tetrachlorobenzo(p)dioxin in MCF-7 human breast cancer cells [64] . The BRCA-1 promoter in resveratrol-treated cells showed reduced association of the aromatic hydrocarbon receptor, DNMT1 and MBD2 [64] .…”

“…Resveratrol (10 and 20 M ) reversed epigenetic silencing of breast cancer 1 ( BRCA-1 ) by the aromatic hydrocarbon receptor agonist 2,3,7,8-tetrachlorobenzo(p)dioxin in MCF-7 human breast cancer cells [64] . The BRCA-1 promoter in resveratrol-treated cells showed reduced association of the aromatic hydrocarbon receptor, DNMT1 and MBD2 [64] . In MCF-7 and MDA-MB-231 breast cancer cells, caffeic acid (1-50 M ) and chlorogenic acid (1-50 M ) induced RAR ␤ promoter demethylation indirectly through increased formation of S-adenosyl-L -homocysteine (a potent inhibitor of DNMT) during the catechol-O -methyltransferase-mediated O -methylation of these dietary catechols [65] .…”

Premature or pathological aging: longevity

“…Pre-treatment with resveratrol increased H4 and H3K9 acetylation, reduced H3K9 methylation and modulated the recruitment of MBD2 to BRCA1 gene promoter in MCF-7 breast cancer treated with tetrachlorobenzene dioxin (PAPOUTSIS et al, 2010). These findings indicate that epigenetic silencing of BRCA1 gene could be prevented with resveratrol, revealing the molecular basis for the development of therapeutic strategies for cancer control.…”

“…• Resveratrol This antagonizes histone modifications induced by dioxin in the BRCA1 gene, suppression of BRCA1 encoded protein expression and reduces DNA fragmentation induced by dioxin in MCF-7 cells in breast cancer (PAPOUTSIS et al, 2010). Pre-treatment with resveratrol increased H4 and H3K9 acetylation, reduced H3K9 methylation and modulated the recruitment of MBD2 to BRCA1 gene promoter in MCF-7 breast cancer treated with tetrachlorobenzene dioxin (PAPOUTSIS et al, 2010).…”

Adverse Effects on Female Human Reproductive Health from Exposure to Endocrine Disruptors: Focus on Endometrial Lesions

“…It is hypothesized that agonists of the AhR, bisphenol A (BPA), and arsenic compounds, induce in tumor suppressor genes epigenetic signatures that mirror those often seen in sporadic breast tumors [43]. Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells [44]. In addition, the co-treatment of MCF-7 breast cancer cells with the dietary compounds 3, 3'-diindolylmethane, a condensation product of indol-3-carbinol found in Brassica vegetables, suggested that naturally occurring modulators of the AhR, such as 3, 3'-diindolylmethane, may be effective agents for dietary strategies against epigenetic activation of COX-2 expression by AhR agonists [45].…”