The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma

Publication date: Available online 31 May 2018
Source:Cancer Cell
Author(s): Matthew J. McBride, John L. Pulice, Hannah C. Beird, Davis R. Ingram, Andrew R. D'Avino, Jack F. Shern, Gregory W. Charville, Jason L. Hornick, Robert T. Nakayama, Enrique M. Garcia-Rivera, Dejka M. Araujo, Wei-Lien Wang, Jen-Wei Tsai, Michelle Yeagley, Andrew J. Wagner, P. Andrew Futreal, Javed Khan, Alexander J. Lazar, Cigall Kadoch
Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

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Teaser

Incorporation of the synovial sarcoma SS18-SSX fusion into BAF complexes results in concomitant eviction of BAF47. McBride et al. show that SS18-SSX retargets BAF complexes from enhancers to polycomb domains to oppose PRC2-mediated repression. Reincorporation of BAF47 upon suppression of SS18-SSX restores enhancer activation but is not required for proliferative arrest.


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