USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma

Halle J. Mallard, Shibiao Wan, Prakriti Nidhi, Yvan D. Hanscom-Trofy, Bhopal Mohapatra, Nicholas T. Woods, Jose Antonio Lopez-Guerrero, Antonio Llombart-Bosch, Isidro Machado, Katia Scotlandi, Natasha F. Kreiling, Megan C. Perry, Sameer Mirza, Donald W. Coulter, Vimla Band, Hamid Band, Gargi Ghosal

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most EWS, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress. The mechanism by which EWS cells override activation of apoptosis or cellular senescence in response to increased replication stress is not known. We show that USP1 is overexpressed in EWS and EWS::FLI1 regulates USP1 transcript levels. USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. Mechanistically, USP1 regulates Survivin (BIRC5/ API4) protein stability and the activation of caspase-9 and caspase-3/7 in response to endogenous replication stress. Notably, USP1 inhibition sensitizes cells to doxorubicin and etoposide treatment. Together, our study demonstrates that USP1 is regulated by EWS::FLI1, the USP1–Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes cells to standard of care chemotherapy.

Original languageEnglish
Pages (from-to)1186-1204
Number of pages19
JournalMolecular Cancer Research
Volume21
Issue number11
DOIs
Publication statusPublished - 2023
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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