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Abrogation of TCDD Induced Epigenetic Silencing of BRCA‐1 by Resveratrol
Author(s) -
Papoutsis Andreas,
Romagnolo Donato,
Selmin Ornella
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.924.4
Subject(s) - aryl hydrocarbon receptor , resveratrol , chromatin immunoprecipitation , epigenetics , dna methylation , histone , cancer research , biology , chromatin , dna damage , chemistry , promoter , microbiology and biotechnology , dna , gene , gene expression , genetics , transcription factor , pharmacology
BRCA‐1 protein is involved in repair of DNA damage. Mutations of the BRCA‐1 gene confer a high risk of developing breast cancer. In sporadic breast cancers BRCA‐1 is silenced in the absence of mutations. 2,3,7,8 tetrachlorodibenzene(p)dioxin (TCDD) is a ligand of the aryl hydrocarbon receptor (AhR) that contributes to this etiology. Resveratrol is a dietary ligand of the AhR with potential protective effects. Activation of the AhR leads to its association with xenobiotic responsive elements (XRE) harbored in the BRCA‐1 promoter. The results of DNA binding studies in MCF‐7 breast cancer cells documented that TCDD induced the association of the AhR to the XRE which was reduced by cotreatment with resveratrol. Western blot analysis revealed that TCDD reduced BRCA‐1 protein expression and that this effect was counteracted by resveratrol. Epigenetic modifications investigated by chromatin immunoprecipitation assays (ChIP) indicated that TCDD facilitated, whereas resveratrol antagonized the recruitment of DNA methyltransferase 1 (DNMT1) and histone deaceytlase 1 (HDAC1). These findings support a model in which resveratrol prevents the assembly of a co‐repressive complex responsible for transcriptional inactivation of BRCA‐1. We are currently investigating changes in DNA methylation induced by TCDD at the BRCA‐1 promoter and the preventative effects of resveratrol. Susan G. Komen Breast Cancer for the Cure