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Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial

Konstantinos V Floros1,2, Carter K Fairchild1,3, Jinxiu Li4

  • 1VCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.

Nature Communications
|November 5, 2025
PubMed

Insights

Synovial sarcoma (SS) is driven by SS18::SSX. A new drug, TAK-981, targets SUMOylation to restore normal cell function, inhibit tumor growth, and improve chemotherapy effectiveness in SS models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Chromatin Biology

Background:

  • Synovial sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein, leading to resistance to current therapies.
  • SS18::SSX disrupts ATP-dependent chromatin remodeling BAF (SWI/SNF) complexes, promoting SS-specific transcription and tumorigenesis.
  • The SS18::SSX oncoprotein activates the SUMOylation pathway, contributing to SS pathogenesis.

Purpose of the Study:

  • To investigate the role of SUMOylation in SS pathogenesis.
  • To evaluate the therapeutic potential of targeting the SUMOylation pathway in SS.
  • To determine if targeting SUMOylation can restore canonical BAF (cBAF) complexes and inhibit SS tumor growth.

Main Methods:

  • Utilized small molecule SUMOylation inhibitor TAK-981 in human and mouse SS models.
  • Assessed the effect of TAK-981 on SMARCE1 de-SUMOylation, cBAF complex restoration, and SS18::SSX-driven transcription.
  • Evaluated tumor inhibition, DNA damage, cell death, and synergy with chemotherapy.

Main Results:

  • TAK-981 de-SUMOylates SMARCE1, stabilizing and restoring cBAF complexes on chromatin.
  • Restoration of cBAF complexes shifts SS models away from SS18::SSX-driven transcription.
  • TAK-981 induced DNA damage, cell death, and tumor inhibition in SS models.
  • TAK-981 synergized with chemotherapy, increasing DNA damage and leading to tumor regression.

Conclusions:

  • Targeting the SUMOylation pathway is a promising therapeutic strategy for SS.
  • SUMOylation plays a critical role in SS pathogenesis by maintaining the SS18::SSX-driven transcriptional program.
  • Restoring cBAF complexes via SUMOylation inhibition represents a novel therapeutic vulnerability in SS.

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