Journal Article

DKFZ-2025-02285

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma.

Floros, K. V. ; Fairchild, C. K. ; Li, J. ; Zhang, K. ; Roberts, J. L. ; Kurupi, R. ; Paudel, D. ; Xing, Y. ; Hu, B. ; Kraskauskiene, V. ; Hosseini, N. ; Shen, S. ; Inge, M. M. ; Smith-Fry, K. ; Li, L. ; Sotiriou, A.DKFZ* ; Dalton, K. M. ; Jose, A. ; Abdelfadiel, E. I. ; Hill, R. D. ; Slaughter, J. M. ; Shende, M. ; Lorenz, M. R. ; Tanaka, N. ; Kajino, T. ; Nelson, M. L. ; Hinojosa, M. R. ; Kehinde, V. A. ; Belvin, B. R. ; Sugiokto, F. G. ; Lai, Z. ; Dimopoulos, A. C. ; Boikos, S. A. ; Stamatouli, A. M. ; Lewis, J. P. ; Manjili, M. H. ; Ebi, H. ; Valerie, K. ; Li, R. ; Poklepovic, A. ; Koblinski, J. E. ; Siggers, T. ; Banito, A.DKFZ* ; Dozmorov, M. G. ; Jones, K. B. ; Radhakrishnan, S. K. ; Faber, A. C.

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-64665-8

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.

Keyword(s): Sarcoma, Synovial: genetics (MeSH) ; Sarcoma, Synovial: metabolism (MeSH) ; Sarcoma, Synovial: drug therapy (MeSH) ; Sarcoma, Synovial: pathology (MeSH) ; Humans (MeSH) ; Sumoylation: drug effects (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Cell Line, Tumor (MeSH) ; Transcriptome (MeSH) ; Oncogene Proteins, Fusion: genetics (MeSH) ; Oncogene Proteins, Fusion: metabolism (MeSH) ; Gene Expression Regulation, Neoplastic: drug effects (MeSH) ; DNA Damage: drug effects (MeSH) ; Transcription Factors: metabolism (MeSH) ; Transcription Factors: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; Neoplasm Proteins: metabolism (MeSH) ; Neoplasm Proteins: genetics (MeSH) ; Chromosomal Proteins, Non-Histone: metabolism (MeSH) ; Chromosomal Proteins, Non-Histone: genetics (MeSH) ; Repressor Proteins: metabolism (MeSH) ; Repressor Proteins: genetics (MeSH) ; Chromatin Assembly and Disassembly (MeSH) ; Oncogene Proteins, Fusion ; Transcription Factors ; DNA-Binding Proteins ; SS18-SSX1 fusion protein ; Neoplasm Proteins ; Chromosomal Proteins, Non-Histone ; Repressor Proteins

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Contributing Institute(s):

1. NWG Weichteilsarkome (B380)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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