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000301550 1001_ $$aHasegawa, Nobuhiko$$b0
000301550 245__ $$aDNA demethylating agents suppress preclinical models of synovial sarcoma.
000301550 260__ $$aAnn Arbor, Mich.$$bASCJ$$c2025
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000301550 520__ $$aSynovial sarcoma is an aggressive soft tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by Polycomb repressive complexes (PRCs) activity. Because KDM2B brings PRC to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacologic inhibition with cytidine analogs 5-aza-2'-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer.
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000301550 650_7 $$2Other$$aCancer
000301550 650_7 $$2Other$$aEpigenetics
000301550 650_7 $$2Other$$aExpression profiling
000301550 650_7 $$2Other$$aGenetics
000301550 650_7 $$2Other$$aOncology
000301550 7001_ $$0P:(DE-He78)b74d7041806f139a13c57351adf92984$$aBenabdallah, Nezha Suzanne$$b1$$eFirst author
000301550 7001_ $$aSmith-Fry, Kyllie$$b2
000301550 7001_ $$aLi, Li$$b3
000301550 7001_ $$aMcCollum, Sarah$$b4
000301550 7001_ $$aLi, Jinxiu$$b5
000301550 7001_ $$aJones, Caelen A$$b6
000301550 7001_ $$0P:(DE-He78)dafca537433ee26708b96d89aba38d29$$aWagner, Lena$$b7
000301550 7001_ $$0P:(DE-He78)6867ed28952f2a9127613528c6a5cf8d$$aDalal, Vineet$$b8
000301550 7001_ $$0P:(DE-He78)4ddf0249a35ca2aff8fb5d00766be420$$aGolde, Viola$$b9$$udkfz
000301550 7001_ $$0P:(DE-He78)5f1c822f3bde55a84c31681d50ce1dd5$$aPejkovska, Anastasija$$b10$$udkfz
000301550 7001_ $$aCarroll, Lara$$b11
000301550 7001_ $$aHaldar, Malay$$b12
000301550 7001_ $$aPollack, Seth M$$b13
000301550 7001_ $$aLowe, Scott W$$b14
000301550 7001_ $$aNielsen, Torsten O$$b15
000301550 7001_ $$0P:(DE-He78)990de6ec6c2f0a40b17ed75162ca19e8$$aBanito, Ana$$b16$$eLast author$$udkfz
000301550 7001_ $$aJones, Kevin B$$b17
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