Histone Acetylation Patterning: A New Direction To Reveal The Clinical Efficacy Of Hdac Inhibitors

Abstract

Recent data highlight the virtually unlimited therapeutic potentials of histone deacetylation (HDAC) inhibitors in treating cancer, inflammatory diseases, and psychiatric disorders. This unlimited therapeutic potential is due to the pleiotropic effects of HDAC inhibitors at cellular and systemic levels. The wide range of effects induced by HDAC inhibitors may have different consequences on histone acetylation that may result in various responses from cell type to cell type and from individual to individual. In this project, we used six different transformed mammalian cell lines from three species and different tissues. We treated them with sodium butyrate (NaBu), vorinostat (SAHA), and trichostatin A (TSA). After that, we used high-resolution two-dimensional polyacrylamide gel electrophoresis to resolve histones and show the global changes in histone acetylation without using antibodies. We found that NaBu, SAHA, and TSA differentially caused an increase in acetylation of core histones in different cell lines. This result indicates that HDAC inhibitors may cause differential epigenetic patterning in different cell types. Thus, we chose seven different HDAC inhibitor drugs, which belong to different classes, to treat the HEK cells. The purpose of this experiment was to test how different HDAC inhibitor drugs affect the histone acetylation in one cell line. We hypothesized that HDAC inhibitor drugs differentially targeted histone subtypes with potentially differing consequences in chromatin structure, gene activity, and clinical outcomes. We found that both canonical and variants histones involved in histone modification and acetylated in a sequence. We proposed that the histone acetylation pattern may be a new way to learn the efficacy of HDAC inhibitor drugs.