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

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.

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Publication Details

Journal
Nature Communications
Published
2025-11-05
DOI
https://doi.org/10.1038/s41467-025-64665-8
Citations
4
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
3.22

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article

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

Janina P. Lewis, Kyllie Smith-Fry, Yanli Xing, Renfeng Li et al.
4 citations
Nature Communications
Ubiquitin and proteasome pathways
3.22
article

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

Janina P. Lewis, Kyllie Smith-Fry, Yanli Xing, Renfeng Li, Durga Paudel, Sosipatros A. Boikos, Zhao Lai, Bin Hu, Madelyn R. Lorenz, Krista M. Dalton, Masoud H. Manjili, Richard Kurupi, Melissa M. Inge, Vita Kraskauskiene, Taisuke Kajino, Carter K. Fairchild, Shanwei Shen, Mary L. Nelson, Afroditi Sotiriou, Kevin B. Jones, Kristoffer Valerie, Konstantinos V. Floros, Ronald D. Hill, Anthony C. Faber, Ana Banito, Mikhail G. Dozmorov, Senthil K. Radhakrishnan, Febri Gunawan Sugiokto, Jennifer E. Koblinski, Trevor Siggers, Nayyerehalsadat Hosseini, Elsamani I. Abdelfadiel, Angeliki M. Stamatouli, Andrew Poklepovic, Alexandros C. Dimopoulos, Hiromichi Ebi, Mayuri Shende, Kun Zhang, Jinxiu Li, Benjamin R. Belvin, Asha Jose, Jane L. Roberts, Mandy R. Hinojosa, Noritaka Tanaka, Li Li, Jamie M. Slaughter, Victor A. Kehinde
article en
4 citations

Abstract

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.

Nature CommunicationsVol. 16(1)
Boston University (US), Boston Medical Center (US), The University of Texas at San Antonio Health Science Center (US), University of Pittsburgh (US), German Cancer Research Center (DE), Virginia Commonwealth University (US), Washington University in St. Louis (US), Heidelberg University (DE), Huntsman Cancer Institute (US), University Hospital Heidelberg (DE), Harokopio University of Athens (GR), Virginia Cancer Institute (US), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), UPMC Hillman Cancer Center (US), Aichi Cancer Center (JP), Georgetown Lombardi Comprehensive Cancer Center, The University of Texas at San Antonio (US), Nagoya University (JP)
U.S. Department of Defense, European Commission, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Openalex Percentile: Top 7%
Ubiquitin and proteasome pathways
3.22
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