%0 Journal Article
%A Floros, Konstantinos V
%A Fairchild, Carter K
%A Li, Jinxiu
%A Zhang, Kun
%A Roberts, Jane L
%A Kurupi, Richard
%A Paudel, Durga
%A Xing, Yanli
%A Hu, Bin
%A Kraskauskiene, Vita
%A Hosseini, Nayyerehalsadat
%A Shen, Shanwei
%A Inge, Melissa M
%A Smith-Fry, Kyllie
%A Li, Li
%A Sotiriou, Afroditi
%A Dalton, Krista M
%A Jose, Asha
%A Abdelfadiel, Elsamani I
%A Hill, Ronald D
%A Slaughter, Jamie M
%A Shende, Mayuri
%A Lorenz, Madelyn R
%A Tanaka, Noritaka
%A Kajino, Taisuke
%A Nelson, Mary L
%A Hinojosa, Mandy R
%A Kehinde, Victor A
%A Belvin, Benjamin R
%A Sugiokto, Febri G
%A Lai, Zhao
%A Dimopoulos, Alexandros C
%A Boikos, Sosipatros A
%A Stamatouli, Angeliki M
%A Lewis, Janina P
%A Manjili, Masoud H
%A Ebi, Hiromichi
%A Valerie, Kristoffer
%A Li, Renfeng
%A Poklepovic, Andrew
%A Koblinski, Jennifer E
%A Siggers, Trevor
%A Banito, Ana
%A Dozmorov, Mikhail G
%A Jones, Kevin B
%A Radhakrishnan, Senthil K
%A Faber, Anthony C
%T Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-02285
%P 9761
%D 2025
%X 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.
%K Sarcoma, Synovial: genetics
%K Sarcoma, Synovial: metabolism
%K Sarcoma, Synovial: drug therapy
%K Sarcoma, Synovial: pathology
%K Humans
%K Sumoylation: drug effects
%K Animals
%K Mice
%K Cell Line, Tumor
%K Transcriptome
%K Oncogene Proteins, Fusion: genetics
%K Oncogene Proteins, Fusion: metabolism
%K Gene Expression Regulation, Neoplastic: drug effects
%K DNA Damage: drug effects
%K Transcription Factors: metabolism
%K Transcription Factors: genetics
%K DNA-Binding Proteins: metabolism
%K DNA-Binding Proteins: genetics
%K Neoplasm Proteins: metabolism
%K Neoplasm Proteins: genetics
%K Chromosomal Proteins, Non-Histone: metabolism
%K Chromosomal Proteins, Non-Histone: genetics
%K Repressor Proteins: metabolism
%K Repressor Proteins: genetics
%K Chromatin Assembly and Disassembly
%K Oncogene Proteins, Fusion (NLM Chemicals)
%K Transcription Factors (NLM Chemicals)
%K DNA-Binding Proteins (NLM Chemicals)
%K SS18-SSX1 fusion protein (NLM Chemicals)
%K Neoplasm Proteins (NLM Chemicals)
%K Chromosomal Proteins, Non-Histone (NLM Chemicals)
%K Repressor Proteins (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41193430
%R 10.1038/s41467-025-64665-8
%U https://inrepo02.dkfz.de/record/305653