SS18–SSX usurps the PRC1.1 repressive complex to drive expression of a synovial sarcoma gene signature.

  • Major finding: SS18–SSX usurps the PRC1.1 repressive complex to drive expression of a synovial sarcoma gene signature.

  • Mechanism: SS18–SSX targets SWI/SNF complexes to unmethylated CpG islands in a KDM2B-dependent manner.

  • Impact: Targeted KDM2B degradation or PRC1.1 inhibition are potential therapies for patients with synovial sarcoma.

The soft-tissue malignancy synovial sarcoma is driven by fusions between the SWI/SNF component SS18 and an SSX transcriptional repressor; these fusions lack DNA binding domains and have been shown to interact with other chromatin regulators such as other components of the SWI/SNF complex and polycomb group proteins. To more precisely elucidate the role of SS18SSX fusions in the regulation of epigenetic networks critical for synovial sarcoma initiation and maintenance, Banito and colleagues transduced the murine synovial sarcoma cell line M5SS1, which expresses the human SS18SSX2 fusion, and murine myoblast cells with a pooled shRNA library targeting 400 epigenetic regulators. Integrated analysis of the shRNA screen and sequencing data revealed that all three of the shRNAs targeting the lysine demethylase Kdm2b, which is a core component of the noncanonical polycomb repressive PRC1.1 complex, were depleted in M5SS1 cells but not in murine myoblast cells. Similarly, KDM2B mRNA and protein expression was shown to be elevated in human synovial sarcoma cell lines and patient synovial sarcoma samples, and depletion of KDM2B, SS18SSX1, or SS18SSX2 resulted in decreased growth, both in vitro and in vivo, and upregulation of mesenchymal differentiation–related genes. CRISPR/Cas9-directed mutagenesis studies revealed that the DNA binding domain of KDM2B and the noncanonical PRC1.1 complex are both required for synovial sarcoma proliferation in vitro, and endogenous SS18–SSX1 was shown to interact with KDM2B and co-occupy unmethylated CpG islands of genes that represent a human synovial sarcoma gene signature, including transcription factors associated with neurogenesis and development. Further, SS18–SSX1 was recruited to target genes in a KDM2B-dependent manner, and high SS18–SSX1/KDM2B co-occupancy was associated with gene activation. These results demonstrate a mechanism by which SS18SSX fusions drive synovial sarcoma and suggest that targeting aberrant de-differentiation programs is a potential therapeutic strategy for patients with synovial sarcoma.

Banito A, Li X, Laporte AN, Roe J-S, Sanchez-Vega F, Huang C-H, et al. The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma. Cancer Cell 2018 Mar 1 [Epub ahead of print].

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