anti-tumor activity of deactylase inhibitors

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The goal of this application is to study the molecular mechanisms underlying the anti-tumor activity of inhibitors of deacetylase enzymes (HDACs). These enzymes, which catalyze the removal of an acetyl group from the lysine residues of proteins, are well recognized to play an important role in the regulation of gene expression, and have also been implicated in malignant transformation. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that block proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. Quite surprisingly, the effects of HDAC inhibitors seem to be somewhat selective for tumor cells and several of these compounds have now entered phase I clinical trials. From a molecular point of view, HDAC inhibition not only results in hyperacetylation of histones but also of key transcription factors such as p53, GATA-1 and estrogen receptoralpha. However thus far, the functional significance of acetylation of non-histone proteins in regulation of cell growth, and the precise mechanisms through which HDAC inhibitors induce tumor cell growth arrest remain poorly understood. We have now identified the p53 gene product as a major determinant of sensitivity to these agents, though in an unexpected way. We found that cells harboring mutations of the p53 gene, which generally confer resistance to treatment with canonical chemotherapeutic agents, are sensitive to the action of the HDAC inhibitor, TSA. We provide evidence that inhibition of HDACs, via TSA treatment, restores function from several types of p53 mutants at least in part due to p53 acetylation, and thus promotes apoptosis. By contrast, in the case of wild-type p53 acetylation of a particular residue, Lysine 320, confers chemo-protection. Based on these data we hypothesize that acetylation differentially influences the activity of wild-type and mutant forms of p53. To address this issue we will take advantage of mice genetically modified in components of the acetylation and of the p53 pathway, of unique cell types, and of a panel of p53 proteins harboring mutations at the known acetylation sites. Furthermore, we propose to identify the cellular deacetylase(s) that targets K320 and to exploit acetylation of this residue for therapeutic purposes. We expect that these studies will generate important information on the pathogenesis of cancer disease, and will provide new leads for the therapy of many types of cancer.