Abstract
Histone deacetylases (HDACs) are epigenetic enzymes that play a central role in gene regulation and are sensitive to the metabolic state of the cell. The cross talk between metabolism and histone acetylation impacts numerous biological processes including development and immune function. HDAC inhibitors are being explored for treating cancers, viral infections, inflammation, neurodegenerative diseases, and metabolic disorders. However, how HDAC inhibitors impact cellular metabolism and how metabolism influences their potency is unclear. Discussed herein are recent applications and future potential of systems biology methods such as high throughput drug screens, cancer cell line profiling, single cell sequencing, proteomics, metabolomics, and computational modeling to uncover the interplay between metabolism, HDACs, and HDAC inhibitors. The synthesis of new systems technologies can ultimately help identify epigenomic and metabolic biomarkers for patient stratification and the design of effective therapeutics.
Highlights
These results demonstrate the mechanism by which therapeutic anticancer histone deacetylase inhibitors (HDACIs) affect metabolism and show the potential of these agents as drugs for cancers that rely on GLUT1 and hexokinase 1 (HXK1) for catabolism
The study discovered that on a single cell level, histone deacetylases (HDACs) inhibition leads to an upregulation of genes involved in acetyl-Coenzyme A (CoA), indicating that HDACI-treated cells are engaged in an acetyl-CoA-deprived state [42]
Inhibitors of histone deacetylases are a promising class of drugs that can reverse aberrant epigenetic changes in these diseases
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. HDAC2 suppress the expression of Fructose-1,6-bisphosphate (FBP1), the rate limiting enzyme in the gluconeogenesis pathway, by deacetylating histone H3K27 in the FBP1 enhancer [17] This downregulates gluconeogenesis, promoting aerobic glycolysis and cancer growth. The cancer cells are forced to utilize amino acid oxidation for energy, which leads to apoptosis [3] These results demonstrate the mechanism by which therapeutic anticancer HDACIs affect metabolism and show the potential of these agents as drugs for cancers that rely on GLUT1 and HXK1 for catabolism. Reductive metabolism of depsipeptide increases inhibition of HDACs. Dietary metabolism can create HDACIs. For instance, fiber is ingested and fermented in the gastrointestinal system into short-chain fatty acids, which can have inhibitory effects on HDACs [1]. The complexity of the metabolic–HDAC interaction network (Figure 1) in a given cell makes it challenging to analyze their interactions, necessitating the use of systems biology technologies
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