MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human Melanoma

Histone modifications, largely regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been recognized as major regulatory mechanisms governing human diseases including cancer. Despite significant effort and recent advances, the mechanism by which the p300 transcriptional coactivator mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the Microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. We find that direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions is coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed Forkhead Box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell growth, which is selectively activated in human melanomas. Targeted chemical inhibition of p300 histone acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor confirmed the critical role of the p300-MITF-FOXM1 axis in melanoma and demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. These data support p300 as a promising novel epigenetic therapeutic target in human melanoma. In order to obtain a comprehensive assessment of p300 downstream effector genes in human melanoma, we performed genome-wide expression profiling analysis of WM983B and SK-Mel5 melanoma cells following p300 depletion. RNA from melanoma cells transduced with either shp300 or scrambled lentiviruses was purified, and the RNA samples were submitted to Boston University Microarray and Sequencing Resource Core Facility for analysis on the Affymetrix GeneChip Human Gene 2.0 ST.