EP300 selectively controls the enhancer landscape of MYCN-amplified neuroblastoma [RNA-seq]

Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastomas (NB) depend on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2?, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound termed ?JQAD1? that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP compensates. Comparing HAT inhibition and EP300-specific degradation, we identified a non-catalytic role for EP300 in promoting MYCN expression and repression of apoptosis. RNA-seq in neuroblastoma model systems treated with JQAD1 or A485