Carcinogenesis Advance Access originally published online on July 14, 2008
Carcinogenesis 2008 29(9):1816-1824; 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
Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512, USA
1 Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
* To whom correspondence should be addressed. Tel: +1 541 737 5086; Fax: +1 541 737 5077; Email: rod.dashwood{at}oregonstate.edu
Histone deacetylase (HDAC) inhibitors have the potential to derepress 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 h of AM exposure, and there was increased binding of the transcription factor Sp3. At a later time, 24 h 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 h after AM treatment and coincided with growth arrest in G1 of the cell cycle. The results are discussed in the context of other anticarcinogenic mechanisms ascribed to garlic organosulfur compounds and the metabolic conversion of such compounds to potential HDAC inhibitors in situ.
Abbreviations: AM, allyl mercaptan; ChIP, chromatin immunoprecipitation; DADS, diallyl disulfide; HAT, histone acetyltransferase; HDAC, histone deacetylase; mRNA, messenger RNA; PCR, polymerase chain reaction; SAC, S-allyl cysteine; SAMC, S-allyl mercaptocysteine; TSA, trichostatin A
Received February 19, 2008; revised July 7, 2008; accepted July 8, 2008.
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