2. Academic Validation
  3. Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability

Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability

  • Nat Struct Mol Biol. 2023 Sep 21. doi: 10.1038/s41594-023-01096-3.
Nezha S Benabdallah 1,  Vineet Dalal 1,  R Wilder Scott 2,  Fady Marcous 1,  Afroditi Sotiriou 1,  Felix K F Kommoss 1 3,  Anastasija Pejkovska 1,  Ludmila Gaspar 1,  Lena Wagner 1,  Francisco J Sánchez-Rivera 4,  Monica Ta 5,  Shelby Thornton 5,  Torsten O Nielsen 5,  T Michael Underhill 2,  Ana Banito 6
Affiliations

Affiliations

  • 1 Soft Tissue Sarcoma Research Group, Hopp Children's Cancer Center, Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 2 Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 3 Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
  • 4 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute, New York, NY, USA.
  • 5 Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 6 Soft Tissue Sarcoma Research Group, Hopp Children's Cancer Center, Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Heidelberg, Germany. a.banito@kitz-heidelberg.de.
PMID: 37735617 DOI: 10.1038/s41594-023-01096-3
Abstract

The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition.

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