Metabolism as a key to HDAC inhibition by dietary constituents

Abstract

Histone deacetylase (HDAC) inhibitors are gaining interest as cancer therapeutic agents. We have pursued this avenue from the perspective of dietary constituents which, after metabolism, alter HDAC activity in cancer cells. Butyrate, a short‐chain fatty acid generated via gut fermentation of dietary fiber, was shown over 30 years ago to affect histone status in erythroleukemia cells, via competitive HDAC inhibition. Cruciferous vegetables such as broccoli contain glucobrassicin, the precursor of sulforaphane (SFN). Metabolism of SFN and other isothiocyanates via the mercapturic acid pathway generates intermediates with HDAC inhibitory activity. Allium vegetables contain various organosulfur compounds which can be converted to small molecule thiols, such as allyl mercaptan, that act as competitive HDAC inhibitors. Natural organoselenium compounds, such as Se‐methylselenocysteine (MSC), are found in selenium‐rich foods such as Brazil nuts. Glutamine transaminase K converts MSC to methylselenopyruvate (MSP), and molecular modeling supported the interaction of MSP with zinc in the HDAC pocket. In colon and prostate cancer cells, MSP was a potent HDAC inhibitor. Thus, various dietary anti‐cancer agents alter HDAC activity and histone acetylation status. Studies supported by NIH grants CA122959, CA090890, CA65525, and P30 ES00210.