Carcinogenesis Advance Access published online on July 14, 2008
Carcinogenesis, doi:10.1093/carcin/bgn165
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Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter
1 Linus Pauling Institute, Oregon State University, Corvallis, OR
2 Dept of Biochemistry & Molecular Biology, New York Medical College, Valhalla, New York
Corresponding author: Dr. Roderick H. Dashwood, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512, USA; Tel: (541) 737-5086; Fax: (541) 737-5077; E-mail: rod.dashwood{at}oregonstate.edu
Histone deacetylase (HDAC) inhibitors have the potential to de-repress epigenetically-silenced genes in cancer cells, leading to cell cycle arrest and apoptosis. In the present study, we screened several garlic-derived small organosulfur compounds for their ability to inhibit HDAC activity in vitro. Among the organosulfur compounds examined, allyl mercaptan (AM) was the most potent HDAC inhibitor. Molecular modeling, structure-activity, and enzyme kinetics studies with purified human HDAC8 provided evidence for a competitive mechanism (Ki = 24 µM AM). In AM-treated human colon cancer cells, HDAC inhibition was accompanied by a rapid and sustained accumulation of acetylated histones in total cellular chromatin. Chromatin immunoprecipitation assays confirmed the presence of hyperacetylated histone H3 on the P21WAF1 gene promoter within 4 hr of AM exposure, and there was increased binding of the transcription factor Sp3. At a later time, 24 hr after AM treatment, there was enhanced binding of p53 in the distal enhancer region of the P21WAF1 gene promoter. These findings suggest a primary role for Sp3 in driving P21 gene expression after HDAC inhibition by AM, followed by the subsequent recruitment of p53. Induction of p21Waf1 protein expression was detected at time-points between 3 and 72 hours after AM treatment, and coincided with growth arrest in G1 of the cell cycle. The results are discussed in the context of other anti-carcinogenic mechanisms ascribed to garlic organosulfur compounds, and the metabolic conversion of such compounds to potential HDAC inhibitors in situ.
Received February 19, 2008; revised July 7, 2008; accepted July 8, 2008.
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