2. Academic Validation
  3. EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

  • Cancer Discov. 2022 Mar 1;12(3):730-751. doi: 10.1158/2159-8290.CD-21-0385.
Adam D Durbin # 1 2 3 4,  Tingjian Wang # 5,  Virangika K Wimalasena 5,  Mark W Zimmerman 1,  Deyao Li 5,  Neekesh V Dharia 1 2 3,  Luca Mariani 6,  Noha A M Shendy 4,  Stephanie Nance 4,  Anand G Patel 7,  Ying Shao 8,  Maya Mundada 4,  Lily Maxham 8,  Paul M C Park 5,  Logan H Sigua 5,  Ken Morita 1,  Amy Saur Conway 1,  Amanda L Robichaud 1,  Antonio R Perez-Atayde 9,  Melissa J Bikowitz 10 11,  Taylor R Quinn 12,  Olaf Wiest 12,  John Easton 8,  Ernst Schönbrunn 10 11,  Martha L Bulyk 3 6 13,  Brian J Abraham 8,  Kimberly Stegmaier 1 2 3,  A Thomas Look 1 2,  Jun Qi 5 14
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2 Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
  • 3 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 4 Division of Molecular Oncology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 6 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 7 Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 8 Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • 9 Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
  • 10 Drug Discovery Department, Moffit Cancer Center, Tampa, Florida.
  • 11 Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida.
  • 12 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana.
  • 13 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 14 Department of Medicine, Harvard Medical School, Boston, Massachusetts.
  • # Contributed equally.
PMID: 34772733 DOI: 10.1158/2159-8290.CD-21-0385
Abstract

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.

Significance: EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner. This article is highlighted in the In This Issue feature, p. 587.

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