Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter
- 9 June 2008
- journal article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 29 (9), 1816-1824
- https://doi.org/10.1093/carcin/bgn165
Abstract
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.Keywords
This publication has 72 references indexed in Scilit:
- Dietary histone deacetylase inhibitors: From cells to mice to manSeminars in Cancer Biology, 2007
- Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cellsInternational Journal of Cancer, 2007
- Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53Nucleic Acids Research, 2007
- Restoration of wild‐type p53 function in human cancer: Relevance for tumor therapyHead & Neck, 2007
- Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis inApcminmiceThe FASEB Journal, 2006
- Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cellsCarcinogenesis: Integrative Cancer Research, 2005
- Thiol-based SAHA analogues as potent histone deacetylase inhibitorsBioorganic & Medicinal Chemistry Letters, 2004
- Diallyl disulfide (DADS) increases histone acetylation and p21waf1/cip1 expression in human colon tumor cell linesCarcinogenesis: Integrative Cancer Research, 2004
- Expression of p21WAF1/Cip1 through Sp1 sites by histone deacetylase inhibitor apicidin requires PI 3-kinase–PKCε signaling pathwayOncogene, 2003
- Design of Specific Inhibitors of Angiotensin-Converting Enzyme: New Class of Orally Active Antihypertensive AgentsScience, 1977