The gcn5 strain shows increased cell death after 1 h, whereas cell death in the wild type strain increases significantly after 2 h. By 4 h propidium iodide uptake is detectable in 6. 7% of the wild type population, compared to 16. 6% of the gcn5 population. Discussion The global decrease in histone modification, particularly methylation and acetylation correlates nearly with an aggressive phenotype and poor prognosis in a number of cancers including prostate, lung and kidney cancer. The ability of HDACis to induce death in a variety of cell lines is well documented, however the mechanisms by which they exert their effects are incompletely under stood. Since many biological processes are regu lated by acetylation, we have used a yeast deletion library screen to gain insights into the cell growth inhibition mechanisms of HDAC inhibitors and to iden tify novel targets for combination treatments with the HDACi CG 1521.

Choosing S. cerevisiae as a model or ganism decreases the complexity, however the high de gree of functional homology among eukaryotes enables the identification of pathways that are important in the response to CG 1521. For example, mitotic analysis after exposure to TSA shows disruption of centromeric het erochromatin, mitotic delay and chromosome segrega tion defects in both fission yeast and mammalian cells. Eukaryotic cells have varied responses to HDACis, which in mammalian cells is partially dictated by the p53 status of the cell lines. For example, treat ment of LNCaP prostate cancer cells, which express wild type p53, with CG 1521 induces G2 M arrest and apoptosis.

In contrast, TSA induces G1 S arrest. These differences in biological response have been attributed to differences in the site specific acetylation of p53, stabilized by these two drugs. However, MCF 7 breast cancer cells, which express wild type p53 and SUM190PT, which express mutant p53 both arrest in G0 G1 after treatment with either CG 1521 or TSA, sug gesting that the complement of HDACs present in the cells also plays a significant role in dictating the bio logical outcome of treatment. Despite the roles of histone acetyltransferases and histone deacetylases in DNA replication and DNA re pair, cytoskeleton dynamics and cell cycle, these func tional classes are not significantly enriched in our screen.

However CG 1521 sensitive strains are significantly enriched in vesicle mediated transport, endocytosis and sensitive to CG 1521. Potentially, these CG 1521 sensitive strains are characterized by decreased histone acetylation and Gcn5 HAT activity as well. This suggests that disrupting the dynamics of acetylation and deacety lation Anacetrapib renders cells sensitive to CG 1521. Strains lacking components of the Gcn5 HAT complexes are very sensitive to CG 1521. Deletion of any of the four components of the histone acetyltransferase module renders S.