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Updated: Feb 9, 2026
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Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA
Published on: September 8, 2021
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EWS/ETS-Driven Ewing Sarcoma Requires BET Bromodomain Proteins
Paradesi Naidu Gollavilli1, Aishwarya Pawar1, Kari Wilder-Romans2
1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, BRBII/III, Philadelphia, Pennsylvania.
Cancer Research
|June 15, 2018
Summary
Ewing sarcoma (EWS) cells depend on BET proteins for their oncogenic transcription. BET inhibitors, like JQ1, show promise in treating EWS by disrupting this dependency and reducing tumor growth.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Ewing sarcoma (EWS) is driven by EWS/ETS fusion transcription factors.
- Targeting EWS/ETS directly has proven difficult, necessitating identification of critical mediators.
- BET bromodomain proteins are potential therapeutic targets in EWS.
Purpose of the Study:
- To investigate the dependency of EWS/ETS-driven transcription on BET bromodomain proteins.
- To evaluate the efficacy of BET inhibitors as a therapeutic strategy for EWS.
Main Methods:
- Knockdown of BRD2/3/4 in EWS cells.
- RNA-sequencing after BRD4 knockdown or JQ1 inhibition.
- Treatment with PROTAC-BET degrader (BETd).
- CRISPR-Cas9 deletion of PHF19.
- In vivo studies using mouse xenograft models.
Main Results:
- EWS/ETS factors form a complex with BRD4; BRD protein knockdown impairs EWS cell phenotype.
- BET inhibition (JQ1/BETd) attenuates EWS/ETS transcriptional signature and reduces proliferation/induces apoptosis via MYC-independent mechanisms.
- PHF19, a PRC2-associated factor, is downregulated by BET inhibition and its knockdown/deletion decreases tumorigenicity and increases sensitivity to JQ1.
- PHF19 expression correlates with poor prognosis in EWS patients.
- JQ1 demonstrates antitumor efficacy in EWS xenograft models.
Conclusions:
- EWS/ETS transcription is dependent on BET epigenetic reader proteins.
- BET inhibitors represent a promising therapeutic strategy for EWS.
- Targeting the BET-PHF19 axis offers a novel therapeutic avenue for EWS treatment.
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