TY  - JOUR
AU  - Floros, Konstantinos V
AU  - Fairchild, Carter K
AU  - Li, Jinxiu
AU  - Zhang, Kun
AU  - Roberts, Jane L
AU  - Kurupi, Richard
AU  - Paudel, Durga
AU  - Xing, Yanli
AU  - Hu, Bin
AU  - Kraskauskiene, Vita
AU  - Hosseini, Nayyerehalsadat
AU  - Shen, Shanwei
AU  - Inge, Melissa M
AU  - Smith-Fry, Kyllie
AU  - Li, Li
AU  - Sotiriou, Afroditi
AU  - Dalton, Krista M
AU  - Jose, Asha
AU  - Abdelfadiel, Elsamani I
AU  - Hill, Ronald D
AU  - Slaughter, Jamie M
AU  - Shende, Mayuri
AU  - Lorenz, Madelyn R
AU  - Tanaka, Noritaka
AU  - Kajino, Taisuke
AU  - Nelson, Mary L
AU  - Hinojosa, Mandy R
AU  - Kehinde, Victor A
AU  - Belvin, Benjamin R
AU  - Sugiokto, Febri G
AU  - Lai, Zhao
AU  - Dimopoulos, Alexandros C
AU  - Boikos, Sosipatros A
AU  - Stamatouli, Angeliki M
AU  - Lewis, Janina P
AU  - Manjili, Masoud H
AU  - Ebi, Hiromichi
AU  - Valerie, Kristoffer
AU  - Li, Renfeng
AU  - Poklepovic, Andrew
AU  - Koblinski, Jennifer E
AU  - Siggers, Trevor
AU  - Banito, Ana
AU  - Dozmorov, Mikhail G
AU  - Jones, Kevin B
AU  - Radhakrishnan, Senthil K
AU  - Faber, Anthony C
TI  - Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-02285
SP  - 9761
PY  - 2025
AB  - 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.
KW  - Sarcoma, Synovial: genetics
KW  - Sarcoma, Synovial: metabolism
KW  - Sarcoma, Synovial: drug therapy
KW  - Sarcoma, Synovial: pathology
KW  - Humans
KW  - Sumoylation: drug effects
KW  - Animals
KW  - Mice
KW  - Cell Line, Tumor
KW  - Transcriptome
KW  - Oncogene Proteins, Fusion: genetics
KW  - Oncogene Proteins, Fusion: metabolism
KW  - Gene Expression Regulation, Neoplastic: drug effects
KW  - DNA Damage: drug effects
KW  - Transcription Factors: metabolism
KW  - Transcription Factors: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - DNA-Binding Proteins: genetics
KW  - Neoplasm Proteins: metabolism
KW  - Neoplasm Proteins: genetics
KW  - Chromosomal Proteins, Non-Histone: metabolism
KW  - Chromosomal Proteins, Non-Histone: genetics
KW  - Repressor Proteins: metabolism
KW  - Repressor Proteins: genetics
KW  - Chromatin Assembly and Disassembly
KW  - Oncogene Proteins, Fusion (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - SS18-SSX1 fusion protein (NLM Chemicals)
KW  - Neoplasm Proteins (NLM Chemicals)
KW  - Chromosomal Proteins, Non-Histone (NLM Chemicals)
KW  - Repressor Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41193430
DO  - DOI:10.1038/s41467-025-64665-8
UR  - https://inrepo02.dkfz.de/record/305653
ER  -