ArticleNature communications2025
Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma.
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Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed.
- Advances in targeted therapies for pediatric tumors.Acta pharmacologica Sinica · 2026Article
- Beyond blacklists: a critical assessment of exclusion set generation strategies and alternative approaches.Bioinformatics (Oxford, England) · 2026Article
- BAF complex-independent gene activation by SS18::SSX.bioRxiv : the preprint server for biology · 2026Article
- Synovial sarcoma reprograms transcription by GBAF activation of polycomb targets and loss of CBAF enhancers.Nature communications · 2025Article
- Molecular and epigenetic oncogenesis in synovial sarcoma: implications for cancer biology, diagnosis and treatment.Oncogene · 2025Review
- Beyond Blacklists: A Critical Assessment of Exclusion Set Generation Strategies and Alternative Approaches.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
47 authors.
Konstantinos V FlorosVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.ORCID http://orcid.org/0000-0003-4916-2257
Carter K Fairchild *VCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Jinxiu Li *Departments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Kun ZhangVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Jane L RobertsVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Richard KurupiVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Durga PaudelVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Yanli XingVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Bin HuDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Vita KraskauskieneDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Nayyerehalsadat HosseiniDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Shanwei ShenDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Melissa M IngeDepartment of Biology, Boston University, Boston, MA, USA.
Kyllie Smith-FryDepartments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Li LiDepartments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Afroditi SotiriouSoft Tissue Sarcoma Research Group, Hopp Children's Cancer Center, Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0002-4534-7185
Krista M DaltonVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Asha JoseVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Elsamani I AbdelfadielVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Ronald D HillVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Jamie M SlaughterVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Mayuri ShendeDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Madelyn R LorenzDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Noritaka TanakaDivision of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.
Taisuke KajinoDivision of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Japan.ORCID http://orcid.org/0000-0002-4826-7690
Mary L NelsonDepartments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.ORCID http://orcid.org/0000-0003-3958-718X
Mandy R HinojosaGreehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, USA.
Victor A KehindeVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.ORCID http://orcid.org/0009-0007-4390-9782
Benjamin R BelvinVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Febri G SugioktoProgram in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0009-0004-2097-2744
Zhao LaiGreehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, USA.
Alexandros C DimopoulosDepartment of Informatics and Telematics, School of Digital Technology, Harokopio University, Athens, Greece.ORCID http://orcid.org/0000-0002-4602-2040
Sosipatros A BoikosGeorgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
Angeliki M StamatouliDivision of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Janina P LewisVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Masoud H ManjiliDepartment of Microbiology & Immunology and Massey Comprehensive Cancer Center, Richmond, VA, USA.ORCID http://orcid.org/0000-0001-7511-2953
Hiromichi EbiRenal Section, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3155-7576
Kristoffer ValerieDepartment of Radiation Oncology and Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Renfeng LiProgram in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.ORCID http://orcid.org/0000-0002-9226-4470
Andrew PoklepovicDepartment of Internal Medicine, Division of Oncology, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Jennifer E KoblinskiDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA.
Trevor SiggersDepartment of Biology, Boston University, Boston, MA, USA.ORCID http://orcid.org/0000-0002-8039-7639
Ana BanitoSoft Tissue Sarcoma Research Group, Hopp Children's Cancer Center, Heidelberg (KiTZ), German Cancer Research Center (DKFZ), Heidelberg, Germany.ORCID http://orcid.org/0000-0003-2188-0003
Mikhail G DozmorovDepartment of Biostatistics, Virginia Commonwealth University, Richmond, VA, USA.
Kevin B JonesDepartments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. kevin.jones@hci.utah.edu.ORCID http://orcid.org/0000-0003-1531-2157
Senthil K RadhakrishnanDepartment of Pathology, Virginia Commonwealth University and Massey Comprehensive Cancer Center, Richmond, VA, USA. senthil.radhakrishnan@vcuhealth.org.ORCID http://orcid.org/0000-0002-5211-9498
Anthony C FaberVCU Philips Institute, Virginia Commonwealth University School of Dentistry and Massey Comprehensive Cancer Center, Richmond, VA, USA. acfaber@vcu.edu.ORCID http://orcid.org/0000-0002-7246-4272
Funding
TISSUE CULTURE---COREP30CA054174 · NCI · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Lei Zheng · 1991 to 2026
$59.1MVirus Vector Shared ResourceP30CA016059 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI Renato Martins · 1985 to 2026
$51.0MTargeting SS18-SSX biology in synovial sarcomagenesisU54CA231652 · NCI · UNIVERSITY OF UTAH · PI JONES, KEVIN BRUCE · 2018 to 2022
$12.0MSUMOylation disruption is toxic for SS18-SSX-driven synovial sarcomaR01CA272710 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI Anthony Charles Faber · 2023 to 2026
$2.2MThe Role of PIAS1 in EBV BiologyR01AI141410 · NIAID · VIRGINIA COMMONWEALTH UNIVERSITY · PI LI, RENFENG · 2019 to 2023
$1.9MIntegrative Training Program in Cancer BiologyT32CA272382 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI Paula Daniela Bos · 2023 to 2026
$1.3MAdvancing Cancer Research Through Next Generation Sequencing at Mays Cancer Center of UT Health San AntonioR50CA265339 · NCI · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Zhao Lai · 2022 to 2026
$957kIllumina NovaSeq 6000 Sequencing SystemS10OD030311 · OD · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI LAI, ZHAO · 2021 to 2021
$600kNCI NIH HHS P30 CA016059NCI NIH HHS P30 CA054174NCI NIH HHS R01 CA272710NCI NIH HHS R50 CA265339NCI NIH HHS T32 CA272382NCI NIH HHS U54 CA231652NIAID NIH HHS R01 AI141410NIH HHS S10 OD030311U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics) 1R01CA272710-01A1
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.
Indexed as
Chromosomal Proteins, Non-HistoneNeoplasm ProteinsOncogene Proteins, FusionRepressor ProteinsSarcoma, SynovialSumoylationTranscriptomeAnimalsCell Line, TumorChromatin Assembly and DisassemblyDNA-Binding ProteinsDNA DamageGene Expression Regulation, NeoplasticHumansMiceTranscription FactorsChromosomal Proteins, Non-HistoneDNA-Binding ProteinsNeoplasm ProteinsOncogene Proteins, FusionRepressor ProteinsSS18-SSX1 fusion proteinTranscription Factors
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