Banito, Ana, Li, Xiang, Laporte, Aimée N., Roe, Jae-Seok, Sanchez-Vega, Francisco, Huang, Chun-Hao, Dancsok, Amanda R., Hatzi, Katerina, Chen, Chi-Chao, Tschaharganeh, Darjus F., Chandwani, Rohit, Tasdemir, Nilgun, Jones, Kevin B., Capecchi, Mario R., Vakoc, Christopher R., Schultz, Nikolaus, Ladanyi, Marc, Nielsen, Torsten O., Lowe, Scott W. (March 2018) The SS18-SSX Oncoprotein Hijacks KDM2B-PRC1.1 to Drive Synovial Sarcoma. Cancer Cell, 33 (3). pp. 527-541. ISSN 1535-6108
Abstract
Summary 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.
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