2. Academic Validation
  3. Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis

Targeting SUMO2 reverses aberrant epigenetic rewiring driven by SS18::SSX fusion oncoproteins and impairs sarcomagenesis

  • EMBO J. 2025 Aug 13. doi: 10.1038/s44318-025-00526-w.
Rema Iyer 1,  Anagha Deshpande 1,  Aditi Pedgaonkar 1,  Pramod Akula Bala 2,  Taehee Kim 3,  Gerard L Brien 4 5,  Darren Finlay 6,  Kristiina Vuori 6,  Alice Soragni 3,  Hiromi I Wetterstein 7,  Rabi Murad 2,  Aniruddha J Deshpande 8
Affiliations

Affiliations

  • 1 Cancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 2 Computational Biology Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 3 Department of Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • 4 Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer University of Edinburgh, Edinburgh, UK.
  • 5 MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
  • 6 Cancer Molecular Therapeutics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 7 Department of Pathology, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine at the University of California, San Diego, La Jolla, CA, USA.
  • 8 Cancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. adeshpande@sbpdiscovery.org.
PMID: 40804185 DOI: 10.1038/s44318-025-00526-w
Abstract

Synovial sarcoma (SySa) is an aggressive soft tissue sarcoma with an urgent need to develop targeted therapies. Here, we exploited specific vulnerabilities created by transcriptional rewiring by the fusion protein SS18::SSX, the sole oncogenic driver in SySa. To uncover genes that are selectively essential for the fitness of SySa cells compared to Other tumor cell lines, we mined the Cancer-Dependency-Map data. Targeted CRISPR library screening of SySa-selective candidates revealed that the small ubiquitin-like modifier 2 (SUMO2) constituted one of the strongest dependencies both in vitro and in vivo. TAK-981, a clinical-stage small-molecule SUMO2 inhibitor potently suppressed growth and colony-forming ability. Transcriptomic profiling showed that SUMO2 inhibition elicited a profound reversal of the gene expression program orchestrated by SS18::SSX fusion. Further, genetic depletion or SUMO2 inhibition reduced global expression levels and chromatin occupancy of the SS18::SSX fusion protein with a concomitant reduction in histone 2A lysine 119 ubiquitination (H2AK119ub), an epigenetic MARK facilitating SySa pathogenesis. Taken together, our study identifies SUMO2 as a novel, selective vulnerability in synovial sarcoma, suggesting new avenues for targeted treatment of soft tissue tumors.

Keywords

SUMO2; Synovial Sarcoma.

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