Journal
BIOCHEMICAL PHARMACOLOGY
Volume 85, Issue 9, Pages 1398-1404Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.02.010
Keywords
Epigenetics; DNA methylation; Sulforaphane; Nrf2; Prostate cancer
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Funding
- NCCIH NIH HHS [R01 AT007065] Funding Source: Medline
- NCI NIH HHS [R01 CA118947] Funding Source: Medline
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Growing evidence suggests epigenetic alteration is involved during the development and progression of prostate cancer. Previously, we found Nrf2, a key regulator of cellular antioxidant defense systems, was silenced through epigenetic mechanism during tumorigenesis in vivo TRAMP mice and in vitro TRAMP Cl cells. Sulforaphane (SFN) in cruciferous vegetable has been demonstrated to be a potent cancer prevention agent for years. The aim of this study is to investigate the potential of SFN to restore Nrf2 expression in TRAMP Cl cells through epigenetic modifications. Bisulfite genomic sequencing results indicated that SFN treatment led to demethylation of the first 5 CpGs in the promoter region of the Nrf2 gene in TRAMP Cl cells. Using methylation DNA immunoprecipitation (MeDIP) assay, SFN significantly reduced the ratio of anti-mecyt antibody binding to the Nrf2 promoter containing the first 5 CpGs. SFN increased mRNA and protein expressions of Nrf2 and Nrf2 downstream target gene NQO-1. In addition, SFN decreased the protein levels of DNMT1 and DNMT3a. SFN treatment also attenuated the protein expression levels of HDACs 1, 4, 5, and 7 while increased the level of active chromatin marker acetyl-Histone 3 (Ac-H3). SFN treatments also increased chromatin-immunoprecipitated DNA of Nrf2 gene promoter using anti-Ac-H3 antibody. Taken together, our current study shows that SFN regulates Nrf2's CpGs demethylation and reactivation in TRAMP Cl cells, suggesting SFN may exert its chemopreventive effect in part via epigenetic modifications of Nrf2 gene with subsequent induction of its downstream anti-oxidative stress pathway. Published by Elsevier Inc.
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