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

Rema Iyer1, Anagha Deshpande1, Aditi Pedgaonkar1

  • 1Cancer Genome and Epigenetics Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.

The EMBO Journal
|August 13, 2025
PubMed

Insights

Researchers identified small ubiquitin-like modifier 2 (SUMO2) as a key dependency in synovial sarcoma (SySa). Inhibiting SUMO2 effectively targets SySa cells, offering a promising new therapeutic strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Synovial sarcoma (SySa) is an aggressive soft tissue cancer driven by the SS18::SSX fusion protein.
  • There is a critical need for targeted therapies against SySa.

Purpose of the Study:

  • To identify genes selectively essential for SySa cell fitness.
  • To explore the therapeutic potential of targeting identified vulnerabilities.

Main Methods:

  • Mined Cancer Dependency Map data for SySa-selective genes.
  • Performed targeted CRISPR library screening.
  • Utilized SUMO2 inhibition with TAK-981.
  • Conducted transcriptomic profiling and epigenetic analysis.

Main Results:

  • Small ubiquitin-like modifier 2 (SUMO2) was identified as a critical dependency in SySa.
  • SUMO2 inhibition potently suppressed SySa cell growth in vitro and in vivo.
  • SUMO2 inhibition reversed the SS18::SSX-driven gene expression program.
  • Targeting SUMO2 reduced SS18::SSX protein levels and H2AK119ub epigenetic marks.

Conclusions:

  • SUMO2 is a novel and selective vulnerability in synovial sarcoma.
  • Targeting SUMO2 presents a promising therapeutic strategy for soft tissue tumors.
Keywords:
SUMO2Synovial Sarcoma

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