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Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter.
Carcinogenesis 2008; 29(9):1816-24C

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.

Authors+Show Affiliations

Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18628250

Citation

Nian, Hui, et al. "Allyl Mercaptan, a Garlic-derived Organosulfur Compound, Inhibits Histone Deacetylase and Enhances Sp3 Binding On the P21WAF1 Promoter." Carcinogenesis, vol. 29, no. 9, 2008, pp. 1816-24.
Nian H, Delage B, Pinto JT, et al. Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. Carcinogenesis. 2008;29(9):1816-24.
Nian, H., Delage, B., Pinto, J. T., & Dashwood, R. H. (2008). Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. Carcinogenesis, 29(9), pp. 1816-24. doi:10.1093/carcin/bgn165.
Nian H, et al. Allyl Mercaptan, a Garlic-derived Organosulfur Compound, Inhibits Histone Deacetylase and Enhances Sp3 Binding On the P21WAF1 Promoter. Carcinogenesis. 2008;29(9):1816-24. PubMed PMID: 18628250.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allyl mercaptan, a garlic-derived organosulfur compound, inhibits histone deacetylase and enhances Sp3 binding on the P21WAF1 promoter. AU - Nian,Hui, AU - Delage,Barbara, AU - Pinto,John T, AU - Dashwood,Roderick H, Y1 - 2008/07/14/ PY - 2008/7/17/pubmed PY - 2008/10/22/medline PY - 2008/7/17/entrez SP - 1816 EP - 24 JF - Carcinogenesis JO - Carcinogenesis VL - 29 IS - 9 N2 - 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. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/18628250/Allyl_mercaptan_a_garlic_derived_organosulfur_compound_inhibits_histone_deacetylase_and_enhances_Sp3_binding_on_the_P21WAF1_promoter_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgn165 DB - PRIME DP - Unbound Medicine ER -