| Epigenetic events, including covalent post-translational modification of histones, have frequently been demonstrated to play critical roles in tumor development and progression. The transcriptional coactivator, p300/CBP, possesses both histone acetyltransferase (HAT) activity as well as scaffolding properties that directly influence transcriptional activation of targeted genes. In order to explore the specific contribution of p300 HAT activity to tumor development and progression, a potent and selective small molecule inhibitor, compound C646, is utilized. C646 inhibits the growth of lineage-specific tumor cell lines including human melanomas through direct transcriptional regulation of cell cycle regulatory proteins. Further evaluation of the p300 HAT transcriptome in human melanoma cells using comprehensive gene expression profiling reveals that p300 HAT activity globally promotes cell cycle progression, nucleosome assembly, and the DNA damage checkpoint through direct transcriptional regulatory mechanisms. Additionally, C646 promotes sensitivity to DNA damaging agents leading to enhanced apoptosis of melanoma cells following combination treatment with cisplatin. Together these data suggest that p300 HAT activity regulates critical growth regulatory pathways in tumors and may serve as a novel therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents. |
