p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma.
| Publication Type | Academic Article |
| Authors | Godfrey L, Regalado B, Schweber S, Hatton C, Wenge D, Wen Y, Boileau M, Wessels M, Qi J, Ott C, Stegmaier K, Rivera M, Armstrong S |
| Journal | EMBO Rep |
| Volume | 26 |
| Issue | 19 |
| Pagination | 4766-4793 |
| Date Published | 09/01/2025 |
| ISSN | 1469-3178 |
| Keywords | Sarcoma, Ewing, Enhancer Elements, Genetic, p300-CBP Transcription Factors, RNA-Binding Protein EWS, Gene Expression Regulation, Neoplastic, Bone Neoplasms, E1A-Associated p300 Protein |
| 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. |
| DOI | 10.1038/s44319-025-00552-z |
| PubMed ID | 40890402 |
| PubMed Central ID | PMC12508431 |