Abstract PR05: Reversing the oncogenic roles of misdirected chromatin remodeling: Disruption of mSWI/SNF (BAF) complexes by the SS18-SSX fusion in human synovial sarcoma

Abstract

Abstract Recent exon- and genome-wide sequencing studies of human cancers have revealed frequent mutations in genes encoding subunits of mSWI/SNF or BAF complexes and implicated them as tumor suppressors. Indeed, we estimate that they are mutated in >20% of human cancers (Kadoch et al, Nature Genetics 2013). Interestingly, the subunits most commonly mutated are not required for chromatin remodeling in vitro and thus may contribute to chromatin regulation in a novel way. One difficultly in understanding the oncogenic role(s) of these complexes is distinguishing primary driving mutations from passenger mutations. To investigate the mechanism underlying oncogenesis, we studied human synovial sarcoma (SS), in which transformation results from a remarkably precise and uniform translocation of exactly 78 amino acids of SSX (SSX1, 2 or 4) to the SS18 protein. In a proteomic study we discovered that SS18 is a dedicated, non-exchangeable subunit of BAF complexes. We demonstrate that the hallmark SS18-SSX fusion incorporates into BAF complexes, evicting both the wild-type SS18 protein and the tumor suppressor, hSNF5 (BAF47), which is known to be biallelically inactivated in malignant rhabdoid tumors. The altered complex binds the Sox2 locus, reversing polycomb-mediated H3K27me3 repression and activating Sox2. Sox2 is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of wild-type SS18 leads to reassembly of wild-type complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a two amino acid hydrophilic region of SSX and hence provides a potential foundation for therapeutic intervention. Citation Format: Cigall Kadoch, Gerald R. Crabtree. Reversing the oncogenic roles of misdirected chromatin remodeling: Disruption of mSWI/SNF (BAF) complexes by the SS18-SSX fusion in human synovial sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR05.