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
  • 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. [email protected].
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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