Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds

Abstract

Histone deacetylase (HDAC) inhibitors reactivate epigenetically-silenced genes in cancer cells, triggering cell cycle arrest and apoptosis. Recent evidence suggests that dietary constituents can act as HDAC inhibitors, such as the isothiocyanates found in cruciferous vegetables and the allyl compounds present in garlic. Broccoli sprouts are a rich source of sulforaphane (SFN), an isothiocyanate that is metabolized via the mercapturic acid pathway and inhibits HDAC activity in human colon, prostate, and breast cancer cells. In mouse preclinical models, SFN inhibited HDAC activity and induced histone hyperacetylation coincident with tumor suppression. Inhibition of HDAC activity also was observed in circulating peripheral blood mononuclear cells obtained from people who consumed a single serving of broccoli sprouts. Garlic organosulfur compounds can be metabolized to allyl mercaptan (AM), a competitive HDAC inhibitor that induced rapid and sustained histone hyperacetylation in human colon cancer cells. Inhibition of HDAC activity by AM was associated with increased histone acetylation and Sp3 transcription factor binding to the promoter region of the P21WAF1 gene, resulting in elevated p21 protein expression and cell cycle arrest. Collectively, the results from these studies, and others reviewed herein, provide new insights into the relationships between reversible histone modifications, diet, and cancer chemoprevention.

Fig. 1

Inhibitors in the HDAC pocket. Binding of TSA (top) and SAHA (bottom) were from structural studies [Finnin et al., 1999]. Accelrys Insight II software was used to model interactions of putative inhibitors, with the following parameters: bidentate binding of the ligand to the zinc atom; H-bond partners for buried polar atoms; avoiding steric conflicts between ligand and enzyme based on a fixed protein; maintaining favorable torsion angles; following the favored positions of TSA and SAHA. SFN-Cys fit the HDAC pocket (center) and had comparable geometry to SAHA in the active site (right), with the α-carboxyl group of the cysteine moiety forming a bidentate ligand with the buried zinc atom (gray sphere). For full details, see [Myzak et al., 2004].

Fig. 2

Organosulfur compounds in garlic. Garlic compounds such as Alliin, Allicin, S-allylcysteine (SAC), S-allyl mercaptocysteine (SAMC), diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) are metabolized to allyl mercaptan (AM), allyl methyl sulfide, and methyl mercaptan. AM was identified as a competitive HDAC inhibitor (K_i = 24 µM with human HDAC8) and induced histone acetylation in colon cancer cells [Nian et al., 2008].

Fig. 3

Allyl mercaptan docked in the HDAC pocket. The interaction of AM with human HDAC8 was simulated using MacroModel v8.5 and Jaguar v5.5 software (Schrödinger), as reported elsewhere [Nian et al., 2008]. AM fit into the enzyme pocket with the sulfhydryl group (yellow) presumably ligated to the catalytic zinc atom (blue sphere).