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EP300 Selectively Controls the Enhancer Landscape of MYCN -Amplified Neuroblastoma

2021; American Association for Cancer Research; Volume: 12; Issue: 3 Linguagem: Inglês

10.1158/2159-8290.cd-21-0385

2159-8290

Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh V. Dharia, Luca Mariani, Noha A.M. Shendy, Stephanie Nance, Anand G. Patel, Ying Shao, Maya Mundada, Lily Maxham, Paul M.C. Park, Logan H. Sigua, Ken Morita, Amy Saur Conway, Amanda L. Robichaud, Antonio R. Pérez‐Atayde, Melissa J. Bikowitz, Taylor R. Quinn, Olaf Wiest, John Easton, E. Schönbrunn, Martha L. Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi,

Ubiquitin and proteasome pathways

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) 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 neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed "JQAD1" that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells.