Targeting SUMOylation promotes cBAF complex stabilization and disruption of the SS18::SSX transcriptome in synovial sarcoma
Year: 2025
Type: article
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.
Source: Nature Communications
Authors: Konstantinos V. Floros, Carter K. Fairchild, Jinxiu Li, Kun Zhang, Jane L. Roberts, Richard Kurupi, Durga Paudel, Yanli Xing, Bin Hu, Vita Kraskauskiene, Nayyerehalsadat Hosseini, Shanwei Shen, Melissa M. Inge, Kyllie Smith-Fry, Li Li, Afroditi Sotiriou, Krista M. Dalton, Asha Jose, Elsamani I. Abdelfadiel, Ronald D. Hill, Jamie M. Slaughter, Mayuri Shende, Madelyn R. Lorenz, Noritaka Tanaka, Taisuke Kajino, Mary L. Nelson, Mandy R. Hinojosa, Victor A. Kehinde, Benjamin R. Belvin, Febri G. Sugiokto, Zhao Lai, Alexandros C. Dimopoulos, Sosipatros A. Boikos, Angeliki M. Stamatouli, Janina P. Lewis, Masoud H. Manjili, Hiromichi Ebi, Kristoffer Valerie, Renfeng Li, Andrew Poklepovic, Jennifer E. Koblinski, Trevor Siggers, Ana Banito, Mikhail G. Dozmorov, Kevin B. Jones, Senthil K. Radhakrishnan, Anthony C. Faber
Institutions: Virginia Commonwealth University, VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University Medical Center, University of Utah, Huntsman Cancer Institute, Washington University in St. Louis, Boston University, German Cancer Research Center, Heidelberg University, University Hospital Heidelberg, National Center for Tumor Diseases, Hopp Children's Cancer Center Heidelberg, Boston Medical Center, Aichi Cancer Center, The University of Texas at San Antonio Health Science Center, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Harokopio University of Athens, Georgetown Lombardi Comprehensive Cancer Center, Nagoya University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Cancer Prevention and Research Institute of Texas, University of Pittsburgh, Virginia Commonwealth University, European Commission, National Institutes of Health, Medical Center, University of Pittsburgh, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Division of Cancer Epidemiology and Genetics, National Cancer Institute
Awards: G1143455775, Mays Cancer Center at UT Health SA, Targeting SS18-SSX biology in synovial sarcomagenesis, Illumina NovaSeq 6000 Sequencing System, G1970983373, G2524726931, G4119534169, G4314932329, G434337789, SUMOylation disruption is toxic for SS18-SSX-driven synovial sarcoma, G5635148292, G5827286289, G5850682332, G5856138607, G6286852046, G7069630344, UTHSCSA Cancer Genome Sequencing and Computation Core, G8486518352, G9000055111, G9000186613, G9000324485, Massey Cancer Center - Cancer Center Support Grant
OpenAlex ID: W4415923563