2. Academic Validation
  3. p300/CBP is an essential driver of pathogenic enhancer activity and gene expression in Ewing sarcoma

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

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. Scott_Armstrong@dfci.harvard.edu.
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z