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Selection-dependent and Independent Generation of CRISPR/Cas9-mediated Gene Knockouts in Mammalian Cells
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BAF complex-independent gene activation by SS18::SSX.
Afroditi Sotiriou1,2,3,4, Jinxiu Li5,6, Sanya Middha1,2,3,4
1Soft-tissue sarcoma research group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Biorxiv : the Preprint Server for Biology
|February 9, 2026
Summary
This study shows that the oncogenic SS18::SSX fusion protein in synovial sarcoma can drive transcription independently of BAF complexes. Targeting coactivators like EP300 offers new therapeutic strategies for fusion-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Synovial sarcoma is driven by the SS18::SSX fusion protein, which alters BAF complex function.
- BAF complexes are thought to be essential for SS18::SSX-driven gene activation.
Purpose of the Study:
- To investigate the requirement of BAF activity for synovial sarcoma cell survival and SS18::SSX transcription.
- To identify alternative mechanisms of SS18::SSX-mediated oncogenic transcription.
Main Methods:
- Targeted degradation and genetic deletion of BAF subunits.
- Analysis of SS18::SSX target gene expression.
- Use of domain-specific SS18::SSX mutants.
- Pharmacologic inhibition of EP300/CREBBP.
Main Results:
- BAF complex loss had minimal impact on sarcoma cell viability and SS18::SSX target gene expression.
- SS18::SSX activates transcription independently of BAF, relying on its C-terminal QPGY-rich domain.
- SS18::SSX interacts with EP300 to promote transcription.
- EP300/CREBBP inhibition suppressed SS18::SSX-driven transcription and reduced cell survival.
Conclusions:
- BAF activity is not essential for SS18::SSX-mediated transcriptional activation in synovial sarcoma.
- Synovial sarcoma relies on coactivator recruitment (e.g., EP300) for oncogenic transcription, independent of BAF.
- Targeting EP300/CREBBP represents a potential therapeutic strategy for synovial sarcoma and other fusion-driven cancers.
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