USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma.
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
received:
02
05
2023
revised:
23
06
2023
accepted:
19
07
2023
medline:
2
11
2023
pubmed:
21
7
2023
entrez:
21
7
2023
Statut:
ppublish
Résumé
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. High USP1 and replication stress levels driven by EWS::FLI1 transcription factor in EWS are vulnerabilities that can be exploited to improve existing treatment avenues and overcome drug resistance.
Identifiants
pubmed: 37478161
pii: 727904
doi: 10.1158/1541-7786.MCR-23-0323
pmc: PMC10618738
doi:
Substances chimiques
Proto-Oncogene Protein c-fli-1
0
Survivin
0
RNA-Binding Protein EWS
0
Oncogene Proteins, Fusion
0
USP1 protein, human
EC 3.4.19.12
Ubiquitin-Specific Proteases
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1186-1204Subventions
Organisme : National Cancer Institute (NCI)
ID : CA263504-01A1
Organisme : National Institute of General Medical Sciences (NIGMS)
ID : GM141232-01A1
Organisme : National Cancer Institute (NCI)
ID : CA188181-01A1
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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