SS18–SSX Drives Synovial Sarcoma by Altering SWI/SNF Composition

Synovial sarcomas are soft-tissue malignancies distinguished by a chromosomal translocation that fuses SS18 to one of 3 closely related genes, SSX1, SSX2, or SSX4. Although it is clear that the SS18–SSX fusion drives synovial sarcoma, the underlying mechanism remains unknown. Kadoch and Crabtree report that SS18 is a stable subunit of SWI/SNF nucleosome remodeling complexes, but in synovial sarcoma, incorporation of SS18–SSX into SWI/SNF complexes displaces wild-type SS18 and the tumor suppressor subunit SNF5 (also known as BAF47 and INI1) from SWI/SNF complexes. SS18–SSX and wild-type SS18 compete for assembly into SWI/SNF complexes, as formation of abnormal SWI/SNF complexes could be reversed and synovial sarcoma cell growth was inhibited by overexpressing wild-type SS18. Knockdown of SS18–SSX or the SWI/SNF ATPase subunit also significantly inhibited synovial sarcoma proliferation, indicating that synovial sarcoma cells were dependent on the activity of aberrant residual SWI/SNF complexes. In fibroblasts, forced SS18–SSX expression or knockdown of SS18 or SNF5 significantly increased transcription of SOX2, a pluripotency gene with known roles in oncogenesis. SOX2 expression was essential for synovial sarcoma cell proliferation and was associated with increased SWI/SNF occupancy and decreased levels of histone H3 lysine 27 trimethylation (H3K27me3) at the SOX2 locus. Remarkably, a 2-amino acid segment that distinguished SSX1, SSX2, and SSX4 from nononcogenic SSX proteins was sufficient for SNF5 ejection and SOX2 induction, providing further support for the role of altered SWI/SNF subunit composition in synovial sarcoma and implicating this SSX region as a potential drug target. The finding that altered gene expression caused by a dysfunctional SWI/SNF complex lacking SS18 and SNF5 underlies SS18–SSX-induced transformation thus not only provides crucial insight into the etiology of synovial sarcoma but also suggests potential therapeutic strategies for this cancer.

Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013;153:71–85.

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