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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月5日

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  • Konstantinos V. Floros,
  • Carter K. Fairchild Jr.,
  • 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

摘要

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.