Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors
Figure 2
Overview of the biological effects of histone deacetylase (HDAC) inhibitors in malignant and transformed cells, using sodium butyrate (NaB) as an example. (a) Simplified schematic representation of the molecular pathways accounting for the clinical potential of HDAC inhibitors in cancer therapy. The acetylation status of histones is regulated by the opposing actions of histone acetyltransferases (HATs) and HDACs. HDAC inhibitors mediate anticancer effects through histone-hyperacetylation-mediated changes () in the expression of certain genes and by directly interacting with numerous key intracellular nonhistone proteins including α-tubulin, heat-shock protein 90, and Ku70. HDAC inhibitors result in transcriptional activation and repression of 2–20% of genes; some of which are associated with differentiation, cell cycle arrest, apoptosis, growth inhibition, and cell death as well as inhibition of cancer cell migration, invasion, and angiogenesis. (b) Biological effects of sodium butyrate (NaB) in cancer and normal cells. (i) Sodium butyrate causes hyperacetylation of histones in H9c2 cardiac myocytes. Cells were differentiated with 10 nM all-trans-retinoic acid for 7 days in low serum media, before 24-hour incubation with 2 and 5 mM sodium butyrate. Total cell lysates were immunoblotted for acetylated histone H3, and unmodified histone H3 was used as a loading control. (ii) Sodium butyrate causes reduced cell viability in K562 human erythroleukemic cells and H9c2 cardiac myocytes. Cells were treated with the indicated concentrations of sodium butyrate for 24 hours, and relative cell viability was measured using the Cell Titer blue (Promega) assay kit. (iii) Sodium butyrate induces apoptosis in K562 cells. Cells were treated with 10 mM sodium butyrate for 24 hours, and caspase 3/7 activity was measured using the Apo-ONE Homogeneous (Promega) assay kit. (iv) Sodium butyrate causes K562 cells to arrest in the G1 phase of the cell cycle. Untreated cells (top) and cells treated with 5 mM sodium butyrate (bottom) for 24 hours were stained with propidium iodide, and the cell cycle distribution was examined by flow cytometry.
