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Updated: May 9, 2025
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
DNA demethylating agents suppress preclinical models of synovial sarcoma
Nobuhiko Hasegawa1,2,3,4, Nezha S Benabdallah5,6,7,8, Kyllie Smith-Fry1,2,3
1Department of Orthopaedics.
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.
Insights
DNA methylation inhibitors disrupt synovial sarcoma growth by altering chromatin and gene expression. These DNMT1 inhibitors show promise as repurposed cancer treatments.
Area of Science:
- Oncology
- Epigenetics
- Cancer Biology
Background:
- Synovial sarcoma is driven by the SS18::SSX oncoprotein, affecting chromatin remodeling.
- The SS18::SSX fusion protein interacts with chromatin modifiers like Polycomb repressive complexes (PRCs).
- Synovial sarcoma exhibits low DNA hypomethylation, suggesting a potential vulnerability.
Purpose of the Study:
- To investigate the impact of disturbing DNA methylation on synovial sarcoma growth.
- To explore the therapeutic potential of DNA methyltransferase 1 (DNMT1) inhibitors in synovial sarcoma.
Main Methods:
- CRISPR/Cas9 targeting and pharmacologic inhibition of DNMT1 using cytidine analogs (decitabine, 5-azacytidine).
- Analysis of genome-wide methylation, SS18::SSX distribution, and gene expression profiles.
- Assessment of drug effects on synovial sarcoma cell line growth and in mouse models.
Main Results:
- DNMT1 inhibition led to decreased genome-wide methylation and SS18::SSX redistribution.
- Altered gene expression included upregulation of tumor suppressor and immune-related genes.
- DNMT1 inhibitors suppressed synovial sarcoma cell growth and reduced tumor burden in mice.
Conclusions:
- Disturbing DNA methylation negatively impacts synovial sarcoma growth.
- DNMT1 inhibitors represent a promising targeted therapy for synovial sarcoma.
- Repurposed DNMT1 inhibitors warrant further clinical investigation for synovial sarcoma treatment.
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