Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma
- Konstantinos V. Floros
- Carter K. Fairchild
- Jinxiu Li
- Kun Zhang
- Jane L. Roberts
- Richard Kurupi
- Durga Paudel
- Yanli Xing
- Bin Hu
- Vita Kraskauskiene
- Nayyerehalsadat Hosseini
- Shanwei Shen
- Melissa M. Inge
- Kyllie Smith-Fry
- Li Li
- Afroditi Sotiriou
- Krista M. Dalton
- Asha Jose
- Elsamani I. Abdelfadiel
- Ronald D. Hill
- Jamie M. Slaughter
- Mayuri Shende
- Madelyn R. Lorenz
- Noritaka Tanaka
- Taisuke Kajino
- Mary L. Nelson
- Mandy R. Hinojosa
- Victor A. Kehinde
- Benjamin R. Belvin
- Febri G. Sugiokto
- Zhao Lai
- Alexandros C. Dimopoulos
- Sosipatros A. Boikos
- Angeliki M. Stamatouli
- Janina P. Lewis
- Masoud H. Manjili
- Hiromichi Ebi
- Kristoffer Valerie
- Renfeng Li
- Andrew Poklepovic
- Jennifer E. Koblinski
- Trevor Siggers
- Ana Banito
- Mikhail G. Dozmorov
- Kevin B. Jones
- Senthil K. Radhakrishnan
- Anthony C. Faber
2025-11-05
Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complexes and amplified expression of SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) complexes that drive an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program. The small molecule SUMOylation inhibitor, TAK-981, de-SUMOylates the cBAF/PBAF component, SMARCE1, stabilizing and restoring cBAF on chromatin, shifting SS models away from SS18::SSX-driven transcription. The result is DNA damage, cell death and tumor inhibition across both human and mouse SS tumor models. TAK-981 synergizes with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX transcriptome, identifying an unappreciated role of SUMOylation in SS and a subsequent therapeutic vulnerability.