BAF complex-independent gene activation by SS18::SSX

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Summary In synovial sarcoma, the BAF subunit SS18 is fused to SSX, a transcriptional repressor, generating the oncogenic SS18::SSX fusion protein. Incorporation of SS18::SSX into BAF complexes leads to their aberrant retargeting to Polycomb-repressed genes via SSX, while simultaneously altering their composition and activity. The presence of BAF at Polycomb target sites is widely assumed to be essential for gene activation. Here, we directly tested the requirement for BAF activity in synovial sarcoma cell survival and SS18::SSX-driven transcription. Using targeted degradation of BAF ATPase subunits and deletion of core components, we show that BAF loss has modest effects on sarcoma cell viability and does not impede SS18::SSX target gene expression. Consistently, deletion of the BAF ATPase subunit Smarca4 does not impair SS18::SSX-driven tumor formation in vivo . Using domain-specific SS18::SSX mutants, we further demonstrate that the fusion can activate oncogenic transcription independently of BAF interaction, and that this activity depends on the C-terminal QPGY-rich domain of SS18. Mechanistically, SS18::SSX promotes transcription by engaging the histone acetyltransferase EP300, independently of BAF. Accordingly, pharmacologic degradation of EP300/CREBBP suppresses SS18::SSX-driven transcriptional programs and impairs synovial sarcoma cell survival. Together, these findings challenge the view that BAF activity is required for SS18::SSX-mediated transcriptional activation and demonstrate that aberrant Polycomb target gene expression is sustained through recruitment of transcriptional coactivators in the absence of BAF. Our work reveals new therapeutic vulnerabilities in synovial sarcoma and suggests broader relevance for targeting coactivator-dependent transcription in fusion-driven cancers. Highlights BAF degradation does not alter SS18::SSX-activated transcriptional programs Direct SS18::SSX transcriptional activation is independent of BAF interaction The SS18 C-terminus engages the co-activator EP300 to promote gene expression Small molecule degraders of EP300/CREBBP abolish SS18::SSX-mediated transcription

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