Profiling HDAC inhibitors and histone modifications in cancer cells

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HDAC inhibitors are currently considered a new class of anti-tumor agents due to their ability to induce differentiation and apoptosis via transcriptional modulation of selected groups of genes. To understand the molecular mechanisms by which HDAC inhibitors mediate anti-tumor activities, we have examined the effects of HDAC inhibitors on global alterations of gene expression as well as on histone modifications. The effects on gene transcription were investigated by whole genome expression profiling in three human tumor cell lines, A549, HCT116 and H1299 treated with four HDAC inhibitors, LAQ824, Mitsui, LAL902 and Trapoxin. Comparison of the data sets results in a common set of 40 genes whose expression is altered by all of the HDAC inhibitors in the three cell lines tested, referred to as potential “HDACi signature”. Further analysis of the expression data found that regulators of both the extrinsic (caspase 8) and the mitochondrial (caspase 9) pathways of apoptosis were induced following HDAC inhibitor treatment. This finding was also confirmed when apoptosis and caspase activity in cancer cells treated with LAQ824 were measured. In addition, in consideration of the role of HDACs in determining chromatin structure, we examined the impact of HDAC inhibitors on post-translational modifications of histones. We found that increases in histone acetylation due to HDAC inhibition are accompanied by increases in histone methylation of K4, K36 and K79 on H3. This suggests that acetylation and methylation of histones occur in a coordinated fashion and together establish epigenetic patterns for specific genes or regions of chromatin. All of these observations provide insights into the mechanisms by which HDAC inhibitors serve as anti-cancer drugs. Furthermore, patterns of gene expression and histone modifications can be used as markers and signatures for monitoring patient responses during the course of HDAC inhibitor therapy.