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

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, Turrent Robert 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

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
JournalCancer Cell
DOIs
Publication statusAccepted/In press - 2018 Jan 1
Externally publishedYes

    Fingerprint

Keywords

  • ATP-dependent chromatin remodeling
  • bivalency
  • chromatin
  • enhancers
  • fusion oncoprotein
  • pediatric cancer
  • polycomb
  • SWI/SNF (BAF) complexes
  • synovial sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

McBride, M. J., Pulice, J. L., Beird, H. C., Ingram, D. R., D'Avino, A. R., Shern, J. F., Charville, G. W., Hornick, J. L., Nakayama, T. R., Garcia-Rivera, E. M., Araujo, D. M., Wang, W. L., Tsai, J. W., Yeagley, M., Wagner, A. J., Futreal, P. A., Khan, J., Lazar, A. J., & Kadoch, C. (Accepted/In press). The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma. Cancer Cell. https://doi.org/10.1016/j.ccell.2018.05.002