| Abstract: |
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. © 2025, Hasegawa et al. |
| Keywords: |
adult; controlled study; human cell; promoter region; genetics; cancer growth; nonhuman; mouse; animal; metabolism; animals; mice; gene expression profiling; tumor volume; neoplasm proteins; animal experiment; animal model; drug effect; pathology; cell line, tumor; dna methylation; chimera; tumor suppressor gene; myelodysplastic syndrome; chromatin; cpg island; tumor protein; tumor cell line; oncogene proteins, fusion; upregulation; synovial sarcoma; sarcoma, synovial; drug therapy; mesenchyme; dna (cytosine-5-)-methyltransferase 1; azacitidine; soft tissue cancer; decitabine; preclinical study; chromatin remodeling; humans; human; male; female; article; crispr-cas9 system; dna (cytosine 5) methyltransferase 1; immune-related gene; crispr associated endonuclease cas9; oncogene fusion protein; dnmt1 protein, human; dnmt1 protein, mouse; ss18-ssx1 fusion protein; synovial sarcoma cell line
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