TY  - JOUR
AU  - Hasegawa, Nobuhiko
AU  - Benabdallah, Nezha Suzanne
AU  - Smith-Fry, Kyllie
AU  - Li, Li
AU  - McCollum, Sarah
AU  - Li, Jinxiu
AU  - Jones, Caelen A
AU  - Wagner, Lena
AU  - Dalal, Vineet
AU  - Golde, Viola
AU  - Pejkovska, Anastasija
AU  - Carroll, Lara
AU  - Haldar, Malay
AU  - Pollack, Seth M
AU  - Lowe, Scott W
AU  - Nielsen, Torsten O
AU  - Banito, Ana
AU  - Jones, Kevin B
TI  - DNA demethylating agents suppress preclinical models of synovial sarcoma.
JO  - The journal of clinical investigation
VL  - 135
IS  - 13
SN  - 0021-9738
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2025-01071
SP  - e190855
PY  - 2025
N1  - #EA:B380#LA:B380# / 2025 Apr 29;135(13):e190855
AB  - 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 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.
KW  - Cancer (Other)
KW  - Epigenetics (Other)
KW  - Expression profiling (Other)
KW  - Genetics (Other)
KW  - Oncology (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40299558
DO  - DOI:10.1172/JCI190855
UR  - https://inrepo02.dkfz.de/record/301550
ER  -