TitleAllyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter.
Publication TypeJournal Article
Year of Publication2008
AuthorsNian H, Delage B, Pinto JT, Dashwood RH
Date Published2008 Sep
KeywordsAcetylation, Allyl Compounds, Binding, Competitive, Cell Cycle, Cell Proliferation, Chromatin Immunoprecipitation, Cyclin-Dependent Kinase Inhibitor p21, Flow Cytometry, Garlic, Gene Expression Regulation, Neoplastic, Histone Deacetylase 1, Histone Deacetylase Inhibitors, Histone Deacetylases, Histones, HT29 Cells, Humans, Immunoblotting, Models, Molecular, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Sp1 Transcription Factor, Sp3 Transcription Factor, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53

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 (K(i) = 24 microM 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 G(1) 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.

Alternate JournalCarcinogenesis
PubMed ID18628250
PubMed Central IDPMC2722850
Grant ListCA122959 / CA / NCI NIH HHS / United States
P01 CA090890 / CA / NCI NIH HHS / United States
P01 CA090890-01A20003 / CA / NCI NIH HHS / United States
P30 ES00210 / ES / NIEHS NIH HHS / United States
R01 CA122959-02 / CA / NCI NIH HHS / United States
CA090890 / CA / NCI NIH HHS / United States
R01 CA065525 / CA / NCI NIH HHS / United States
R01 CA122959 / CA / NCI NIH HHS / United States
R01 CA065525-10 / CA / NCI NIH HHS / United States
P01 CA090890-01A29001 / CA / NCI NIH HHS / United States
CA065525 / CA / NCI NIH HHS / United States