DNA demethylating agents suppress preclinical models of synovial sarcoma
Synovial sarcoma is an aggressive soft-tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by polycomb repressive complex activity. Because KDM2B brings polycomb repressive complex to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacological inhibition with cytidine analogs 5-aza-2'-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer.
Authors
- Kyllie Smith-Fry
- Anastasija Pejkovska (ORCID: https://orcid.org/0000-0002-8727-544X)
- Sarah McCollum (ORCID: https://orcid.org/0000-0001-7911-8383)
- Scott W. Lowe (ORCID: https://orcid.org/0000-0002-5284-9650)
- Seth M. Pollack (ORCID: https://orcid.org/0000-0002-2466-0607)
- Vineet Dalal
- Nezha S. Benabdallah (ORCID: https://orcid.org/0000-0001-6925-826X)
- Kevin B. Jones (ORCID: https://orcid.org/0000-0003-1531-2157)
- Ana Banito (ORCID: https://orcid.org/0000-0003-2188-0003)
- Lara Carroll (ORCID: https://orcid.org/0000-0002-8232-7386)
- Torsten O. Nielsen (ORCID: https://orcid.org/0000-0003-3769-2517)
- Viola Golde (ORCID: https://orcid.org/0000-0002-0880-4121)
- Lena Wagner
- C. Jones
- Li Li (ORCID: https://orcid.org/0000-0003-0935-8634)
- Jinxiu Li (ORCID: https://orcid.org/0000-0001-7303-1498)
- Malay Haldar (ORCID: https://orcid.org/0000-0003-3776-0516)
- Nobuhiko Hasegawa
Institutions
- Northwestern University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Vancouver Coastal Health (CA)
- University of British Columbia (CA)
- German Cancer Research Center (DE)
- University of Utah (US)
- Heidelberg University (DE)
- Huntsman Cancer Institute (US)
- Edinburgh Cancer Research (GB)
- Juntendo University (JP)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Vancouver Coastal Health Research Institute (CA)
- University of Pennsylvania (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1172/jci190855
- Citations
- 3
- Primary Topic
- Sarcoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.56
Funders
- Memorial Sloan-Kettering Cancer Center
- Deutsches Krebsforschungszentrum
- European Commission
- National Institutes of Health
- Japan Society for the Promotion of Science
- National Cancer Institute