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

Cancer Cell. 2018 Jun 11;33(6):1128-1141.e7. doi: 10.1016/j.ccell.2018.05.002. Epub 2018 May 31.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Enhancer Elements, Genetic / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques / methods
  • HEK293 Cells
  • Humans
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • SMARCB1 Protein / genetics*
  • SMARCB1 Protein / metabolism
  • Sarcoma, Synovial / genetics*
  • Sarcoma, Synovial / metabolism
  • Sarcoma, Synovial / pathology
  • Whole Exome Sequencing / methods

Substances

  • Chromatin
  • Oncogene Proteins, Fusion
  • SMARCB1 Protein
  • SS18-SSX1 fusion protein