Expression profile of melanoma cells following p300 HAT inhibition

ABSTRACT: 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. We have used a recently reported small molecule inhibitor of p300 HAT activity, C646, to explore the specific contribution of p300/CBP HAT activity to tumor development and progression. We find that 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 our 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. Keywords: p300, small molecule inhibitor, melanoma WM35 cells grown under normal culture conditions were treated for 6 and 24 hours with compound C646 to block p300 HAT activity. A vehicle control (DMSO) was included at each time point. RNA was extracted from all 4 samples using the Qiagen RNeasy kit. RNA quality check, labeling, hybridization, initial data processing and analysis was performed by the JHMI Microarray Core Facility. Affymetrix GeneChip Human Exon 1.0 ST Array was used for this study.

ORGANISM(S): Homo sapiens

SUBMITTER: Alani Rhoda 

PROVIDER: S-ECPF-GEOD-45981 | biostudies-other |

REPOSITORIES: biostudies-other