Histone and Non-Histone Targets of Dietary Deacetylase Inhibitors

Abstract

Acetylation is an important, reversible post-translational modification affecting histone and non-histone proteins with critical roles in gene transcription, DNA replication, DNA repair, and cell cycle progression. Key regulatory enzymes include histone deacetylase (HDACs) and histone acetyltransferases (HATs). Overexpressed HDACs have been identified in many human cancers, resulting in repressed chromatin states that interfere with vital tumor suppressor functions. Inhibition of HDAC activity has been pursued as a mechanism for re-activating repressed genes in cancers, with some HDAC inhibitors showing promise in the clinical setting. Dietary compounds and their metabolites also have been shown to modulate HDAC activity or expression. Out of this body of research, attention increasingly has shifted towards non-histone targets of HDACs and HATs, such as transcriptions factors, hormone receptors, DNA repair proteins, and cytoskeletal components. These aspects are covered in present review, along with the possible clinic significance. Where such data are available, examples are cited from the literature of studies with short chain fatty acids, polyphenols, isoflavones, indoles, organosulfur compounds, organoselenium compounds, sesquiterpene lactones, isoflavones, and various miscellaneous agents. By virtue of their effects on both histone and non-histone proteins, dietary chemopreventive agents modulate the cellular acetylome in ways that are only now becoming apparent. A better understanding of the molecular mechanisms will likely enhance the potential to more effectively combat diseases harboring altered epigenetic landscapes and dysregulated protein signaling. Dietary chemopreventive agents modulate the cellular acetylome by affecting both histone and non-histone proteins, which will likely enhance their potential to more effectively combat diseases harboring altered epigenetic landscapes.

Therapeutic Potential for Natural Product HDAC Inhibitors in Heart Failure

“…HDACi, and other compounds, derived from plants, herbs, and foods stuffs are known to be bioactive compounds [15]. Bioactive HDACi as well as their descriptions and specifications can be found in some detail [49,50]. Cyclic peptide and shortchain fatty acid HDACi are the more familiar types of bioactive HDACi.…”

“…Other bioactive compounds from foods have been identified that regulate HDAC activity, including curcumin and resveratrol [50,52,53]. Resveratrol has been shown to regulate Sirtuins and has been extensively reviewed.…”

“…For instance, curcumin was reported to inhibit p300 HAT activity thus inhibiting GATA4 transcriptional activation and hypertrophic gene expression; cardiac function was subsequently improved in a rodent model of hypertension [54]. Sulforaphane is an HDACi found in broccoli and has been shown to inhibit HDAC activity and increase histone H3 and H4 acetylation in cells, mice and man [50,53,56,57].…”

“…More recently, grape seed procyanidin extract was found to significantly inhibit HDAC activity in rat liver, concomitant with reductions in serum triglycerides [58]. Indeed, the field of nutrigenomics and nutri-epigenetics has rapidly advanced in the last decade leading to increased reports demonstrating the potential impact for food compounds in the regulation of epigenetic marks and gene expression [49,50].…”

“…Most of these studies however, have focused on bioactive food compounds in the treatment or prevention of cancer [49,50,59]; limited studies have examined dietary HDAC inhibitors in the regulation of cardiovascular disease.…”