Salt-Inducible Kinase 1 is a potential therapeutic target in Desmoplastic Small Round Cell Tumor.
Journal
Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004
Informations de publication
Date de publication:
20 Apr 2022
20 Apr 2022
Historique:
received:
26
10
2021
accepted:
01
04
2022
revised:
28
03
2022
entrez:
21
4
2022
pubmed:
22
4
2022
medline:
22
4
2022
Statut:
epublish
Résumé
Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive malignant cancer caused by a chromosomal translocation t(11;22)(p13;q12) that produces an oncogenic transcription factor, EWSR1-WT1. EWSR1-WT1 is essential for the initiation and progression of DSRCT. However, the precise mechanism by which EWSR1-WT1 drives DSRCT oncogenesis remains unresolved. Through our integrative gene expression analysis, we identified Salt Inducible Kinase 1 (SIK1) as a direct target of EWSR1-WT1. SIK1 as a member of the AMPK related kinase is involved in many biological processes. We showed that depletion of SIK1 causes inhibition of tumor cell growth, similar to the growth inhibition observed when EWSR1-WT1 is depleted. We further showed that silencing SIK1 leads to cessation of DNA replication in DSRCT cells and inhibition of tumor growth in vivo. Lastly, combined inhibition of SIK1 and CHEK1with small molecule inhibitors, YKL-05-099 and prexasertib, respectively, showed enhanced cytotoxicity in DSRCT cells compared to inhibition of either kinases alone. This work identified SIK1 as a new potential therapeutic target in DSRCT and the efficacy of SIK1 inhibition may be improved when combined with other intervention strategies.
Identifiants
pubmed: 35443736
doi: 10.1038/s41389-022-00395-6
pii: 10.1038/s41389-022-00395-6
pmc: PMC9021191
doi:
Types de publication
Journal Article
Langues
eng
Pagination
18Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222856
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : 1R01CA222856
Organisme : Louisiana Board of Regents (Board of Regents)
ID : LEQSF(2017-20)-RD-A-18 (S.B.L.)
Informations de copyright
© 2022. The Author(s).
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