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@ARTICLE{Floros:305653,
author = {K. V. Floros and C. K. Fairchild and J. Li and K. Zhang and
J. L. Roberts and R. Kurupi and D. Paudel and Y. Xing and B.
Hu and V. Kraskauskiene and N. Hosseini and S. Shen and M.
M. Inge and K. Smith-Fry and L. Li and A. Sotiriou$^*$ and
K. M. Dalton and A. Jose and E. I. Abdelfadiel and R. D.
Hill and J. M. Slaughter and M. Shende and M. R. Lorenz and
N. Tanaka and T. Kajino and M. L. Nelson and M. R. Hinojosa
and V. A. Kehinde and B. R. Belvin and F. G. Sugiokto and Z.
Lai and A. C. Dimopoulos and S. A. Boikos and A. M.
Stamatouli and J. P. Lewis and M. H. Manjili and H. Ebi and
K. Valerie and R. Li and A. Poklepovic and J. E. Koblinski
and T. Siggers and A. Banito$^*$ and M. G. Dozmorov and K.
B. Jones and S. K. Radhakrishnan and A. C. Faber},
title = {{T}argeting {SUMO}ylation promotes c{BAF} complex
stabilization and disruption of the {SS}18::{SSX}
transcriptome in synovial sarcoma.},
journal = {Nature Communications},
volume = {16},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {DKFZ-2025-02285},
pages = {9761},
year = {2025},
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.},
keywords = {Sarcoma, Synovial: genetics / Sarcoma, Synovial: metabolism
/ Sarcoma, Synovial: drug therapy / Sarcoma, Synovial:
pathology / Humans / Sumoylation: drug effects / Animals /
Mice / Cell Line, Tumor / Transcriptome / Oncogene Proteins,
Fusion: genetics / Oncogene Proteins, Fusion: metabolism /
Gene Expression Regulation, Neoplastic: drug effects / DNA
Damage: drug effects / Transcription Factors: metabolism /
Transcription Factors: genetics / DNA-Binding Proteins:
metabolism / DNA-Binding Proteins: genetics / Neoplasm
Proteins: metabolism / Neoplasm Proteins: genetics /
Chromosomal Proteins, Non-Histone: metabolism / Chromosomal
Proteins, Non-Histone: genetics / Repressor Proteins:
metabolism / Repressor Proteins: genetics / Chromatin
Assembly and Disassembly / Oncogene Proteins, Fusion (NLM
Chemicals) / Transcription Factors (NLM Chemicals) /
DNA-Binding Proteins (NLM Chemicals) / SS18-SSX1 fusion
protein (NLM Chemicals) / Neoplasm Proteins (NLM Chemicals)
/ Chromosomal Proteins, Non-Histone (NLM Chemicals) /
Repressor Proteins (NLM Chemicals)},
cin = {B380},
ddc = {500},
cid = {I:(DE-He78)B380-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41193430},
doi = {10.1038/s41467-025-64665-8},
url = {https://inrepo02.dkfz.de/record/305653},
}