EWS::FLI1 gene fusions underlie an aggressive subset of Ewing sarcoma (EWS). DNA replication stress is abundant in EWS::FLI1-driven EWS, and the mechanism by which EWS cells survive that stress is unknown. In their study, Mallard and colleagues used RT-qPCR arrays and shRNA-mediated EWS::FLI1 ablation to demonstrate that EWS::FLI1 facilitates RNA and protein expression of ubiquitin-specific peptidase 1 (USP1), a deubiquitylase. ChIP RT-qPCR and public ChIP-sequencing and CUT&RUN data analysis suggested EWS::FLI1 localizes to the USP1 promoter and directly promotes its transcription. Genetic and pharmacologic USP1 inhibition slowed S-phase entry and progression and induced cell death in EWS::FLI1-expressing EWS cells. Tandem mass tag mass spectrometry using USP1 shRNA-expressing EWS cells revealed that USP1 augments anti-apoptotic Survivin expression, which was confirmed by Western blotting after genetic or pharmacologic USP1 inhibition. Accordingly, USP1 inhibition enhanced activities of caspases 3, 7, and 9 in EWS::FLI1-expressing EWS cells, and sensitized the cells...
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1 November 2023
Highlights|
November 01 2023
Selected Articles from This Issue
Online ISSN: 1557-3125
Print ISSN: 1541-7786
©2023 American Association for Cancer Research
2023
American Association for Cancer Research
Mol Cancer Res (2023) 21 (11): 1121.
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Citation
Selected Articles from This Issue. Mol Cancer Res 1 November 2023; 21 (11): 1121. https://doi.org/10.1158/1541-7786.MCR-21-11-HI
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