Cancer cells are generally transformed by virtue of a number of (inherited and/or acquired) gene mutations that alter normal patterns of cell proliferation and cell differentiation, and program cell death. Most transformed cells don't lose the capacity to arrest cell growth, differentiate, and/or undergo cell death under appropriate environmental stimuli. Over the past several years, our laboratory has discovered a group of agents, hybrid polar hydroxamic acids, which selectively target histone deacetylases and cause transformed cell-growth arrest, terminal differentiation, apoptosis and/or cell death. The lead compound suberoylanilide hydroxamic acid (SAHA), is in Phase I and Phase II clinical trials in patients with both solid tumors and hematological malignancies; and has shown significantly anticancer effects at doses that are well tolerated by patients. The goals of our continuing research are to explore the mechanisms by which these HDAC inhibitors arrest growth and/or induce cell death of transformed cells with relatively little or no toxic effects on normal cells.
In any given cell, only a proportion of genes are expressed. The regulation of gene expression is determined in large part by the structure of the chromatin proteins around which DNA is wrapped, referred to as epigenetic gene regulation. Post-translation modification of histones of chromatin are important in regulating gene expression. Among the most extensively studied of these epigenetic modifications are those which involve acetylation and deacetylation of the lysines in the tails of the core histones. The acetylation and deacetylation of these lysines is controlled by the action of 2 families of enzymes, histone deacetylases (HDAC) and histone acetylase transferases (HATs). In addition to histones, many proteins involved as transcription factors, cell cycle signaling factors, and proteins involved in programmed cell death are substrates for HDACs. Acetylation of these proteins is associated with alterations of their structure and function.
Contrary to what might be anticipated by the wide distribution of HDACs in the chromatin proteins, inhibition of these enzymes alters the transcription of relatively few of the expressed genes (2 to 10 percent) in any given transformed cell. Among genes that are transcriptionally upregulated by HDAC inhibitors is the p21 gene, which plays an important role in the regulation of cell cycle progression through the G1 phase of the cell cycle. We are currently exploring in detail the basis of the selectivity in altering a gene transcription consequent to HDAC inhibition.
Further, we are studying the basis of the resistance of normal cells and sensitivity of transformed cells to HDAC inhibitors. Normal cells are as much as tenfold more resistant to HDAC inhibitors than transformed cells. This is not due to a failure of HDAC inhibitors to be active in normal cells, since in both normal and transformed cells HDAC inhibitors cause the accumulation of acetylated histones. We have found that HDAC inhibitors can cause caspase independent transformed cell death. The HDAC inhibitors induce the accumulation of reactive oxygen species that the level of the redox protein, thioredoxin (Trx), is critical in determining the response of normal and transformed cells to HDAC inhibitors. Trx is a scavenger of Ros, and HDACi increase Trx levels in normal but not transformed cells. Currently, we are studying the mechanism of HDAC inhibitor-induced Trx in normal but not transformed cells.
Our laboratory personnel include 2 postdoctoral PhD fellows, 2 MD/PhD fellows, and 2 experienced research assistants, who have been with the laboratory for 20-plus years.
