β-catenin S45F mutation results in apoptotic resistance.
Abdominal Neoplasms
/ genetics
Adenomatous Polyposis Coli
/ genetics
Apoptosis
/ genetics
Cell Line, Tumor
Core Binding Factor Alpha 3 Subunit
/ genetics
Down-Regulation
Fibromatosis, Aggressive
/ genetics
Gene Expression Profiling
/ methods
Gene Expression Regulation, Neoplastic
HEK293 Cells
Humans
Mutation, Missense
Wnt Signaling Pathway
/ genetics
beta Catenin
/ genetics
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
07
01
2020
accepted:
25
06
2020
pubmed:
12
7
2020
medline:
1
12
2020
entrez:
12
7
2020
Statut:
ppublish
Résumé
Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.
Identifiants
pubmed: 32651460
doi: 10.1038/s41388-020-1382-5
pii: 10.1038/s41388-020-1382-5
pmc: PMC7441052
doi:
Substances chimiques
Core Binding Factor Alpha 3 Subunit
0
beta Catenin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5589-5600Subventions
Organisme : NCI NIH HHS
ID : U54 CA168512
Pays : United States
Organisme : NCI NIH HHS
ID : K22 CA187931
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
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