The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma

Synovial sarcoma is an aggressive cancer invariably associated with a chromosomal translocation involving genes encoding the SWI-SNF complex component SS18 and an SSX (SSX1 or SSX2) transcriptional repressor. Using functional genomics, we identify KDM2B, a histone demethylase and component of a non-canonical polycomb repressive complex 1 (PRC1.1), as selectively required for sustaining synovial sarcoma cell transformation. SS18-SSX1 physically interacts with PRC1.1 and co-associates with SWI/SNF and KDM2B complexes on unmethylated CpG islands. Via KDM2B, SS18-SSX1 binds and aberrantly activates expression of developmentally regulated genes otherwise targets of polycomb-mediated repression, which is restored upon KDM2B depletion, leading to irreversible mesenchymal differentiation. Thus, SS18-SSX1 deregulates developmental programs to drive transformation by hijacking a transcriptional repressive complex to aberrantly activate gene expression. [Display omitted] •An RNAi screen identifies KDM2B as an epigenetic dependency in synovial sarcoma•KDM2B depletion abolishes neurogenic programs inducing mesenchymal differentiation•KDM2B-PRC1.1 recruits SS18-SSX and SWI/SNF to unmethylated CpG islands•SS18-SSX hijacks a repressive complex to aberrantly activate gene expression Banito et al. show that SS18-SSX fusions characteristic of synovial sarcoma associate with KDM2B-PRC1.1, a non-canonical polycomb repressive complex 1, to aberrantly activate the expression of developmentally regulated transcription factors that are normally targets of polycomb-mediated gene repression.