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Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma

Cigall Kadoch1, Gerald R Crabtree

  • 1Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Cell
|April 2, 2013
PubMed

Insights

Mutations in SWI/SNF (BAF) complexes are common in human cancers. In synovial sarcoma, the SS18-SSX fusion protein disrupts BAF complexes, activating the Sox2 gene and driving tumor growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Over 20% of human tumors harbor mutations in SWI/SNF (BAF) complexes.
  • Synovial sarcoma (SS) is characterized by a specific translocation involving the SS18 and SSX genes.

Purpose of the Study:

  • To elucidate the molecular mechanism by which the SS18-SSX fusion protein drives synovial sarcoma.
  • To investigate the role of BAF complexes and Sox2 in SS pathogenesis.

Main Methods:

  • Studied human synovial sarcoma (SS) cell models.
  • Analyzed the assembly of BAF complexes and their interaction with the Sox2 locus.
  • Assessed the impact of SS18-SSX on polycomb-mediated repression and Sox2 activation.

Main Results:

  • The SS18-SSX fusion protein forms an aberrant BAF complex lacking BAF47 (hSNF5).
  • This altered complex targets the Sox2 locus, reversing repression and leading to Sox2 activation, which is crucial for SS proliferation.
  • Restoring wild-type SS18 levels reassembles functional BAF complexes, represses Sox2, and halts proliferation.

Conclusions:

  • The SS18-SSX fusion protein hijacks BAF complexes to activate Sox2, a key driver of synovial sarcoma.
  • This oncogenic mechanism is dependent on a minimal SSX sequence, suggesting a targeted therapeutic approach.

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