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

Publication date: Available online 1 March 2018
Source:Cancer Cell
Author(s): Ana Banito, Xiang Li, Aimée N. Laporte, Jae-Seok Roe, Francisco Sanchez-Vega, Chun-Hao Huang, Amanda R. Dancsok, Katerina Hatzi, Chi-Chao Chen, Darjus F. Tschaharganeh, Rohit Chandwani, Nilgun Tasdemir, Kevin B. Jones, Mario R. Capecchi, Christopher R. Vakoc, Nikolaus Schultz, Marc Ladanyi, Torsten O. Nielsen, Scott W. Lowe
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.

Graphical abstract

Teaser

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.


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