p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma

  • EMBO Rep. 2025 Oct;26(19):4766-4793. doi: 10.1038/s44319-025-00552-z.
Laura C Godfrey  1 ,  Brandon Regalado  1 ,  Sydney R Schweber  1 ,  Charles Hatton  1 ,  Daniela V Wenge  1 ,  Yanhe Wen  1 ,  Meaghan Boileau  1 ,  Maria Wessels  1  2 ,  Jun Qi  3 ,  Christopher J Ott  4  5  6 ,  Kimberly Stegmaier  1  5 ,  Miguel N Rivera  5  7 ,  Scott A Armstrong  8
Affiliations
  • 1. Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.
  • 2. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4. Massachusetts General Hospital Cancer Center, Charlestown, MA, USA.
  • 5. Broad Institute of MIT & Harvard, Cambridge, MA, USA.
  • 6. Harvard Medical School, Boston, MA, USA.
  • 7. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • 8. Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 40890402 DOI: 10.1038/s44319-025-00552-z
Abstract

The t(11;22) translocation encodes the EWS::FLI1 fusion oncoprotein which is the primary driver of Ewing sarcoma. EWS::FLI1 creates unique, de novo pathogenic enhancers that drive gene expression and are a central mechanism of oncogenesis. Which chromatin regulatory proteins are critical to this mechanism is understudied. Here, we perform a comparative analysis of the function of the chromatin complexes MLL3/4 and p300/CBP in EWS::FLI1-mediated gene regulation. Using EWS::FLI1 degradation models, we define a subset of EWS::FLI1-sensitive enhancers whose activity correlates with p300/CBP function. We perturb both chromatin complexes to establish that in contrast to MLL3/4, p300/CBP is a critical regulator of EWS::FLI1-driven enhancer activity and downstream gene expression. We also show that p300/CBP small-molecule inhibition decelerates tumor growth in vivo. Our work highlights the context-dependent nature of chromatin protein activity at oncogenic enhancers and reveals p300/CBP as an important regulator of Ewing sarcoma.

Keywords
EWS::FLI1; Enhancers; Ewing Sarcoma; Histone Modifications; p300/CBP.
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