Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma
- Dana Farber Cancer Institute, United States
- University of Pennsylvania, United States
- University College Dublin, Ireland
- Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Netherlands
- Dana-Farber Cancer Institute, United States
- German Cancer Consortium (DKTK), Germany
- Cold Spring Harbor Laboratory, United States
Abstract
Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease.
Data availability
All next-generation sequencing datasets generated in association with this work have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE113229
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Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcomaNCBI Gene Expression Omnibus, GSE113229.
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Author details
Funding
National Cancer Institute (CA176745)
- Scott A Armstrong
Alex's Lemonade Stand Foundation for Childhood Cancer
- Scott A Armstrong
European Molecular Biology Organization (ALTF-1235-2015)
- Gerard L Brien
Irish Cancer Society (CRF18BRI)
- Gerard L Brien
National Cancer Institute (CA066996)
- Scott A Armstrong
National Cancer Institute (CA204915)
- Scott A Armstrong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were performed according to approved institutional animal care and use committee (IACUC) protocols at the Dana Farber Cancer Institute.
Copyright
© 2018, Brien et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma
eLife 7:e41305.
https://doi.org/10.7554/eLife.41305
