Oncogene, 2020-08, Vol.39 (34), p.5589-5600
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.
Core Binding Factor Alpha 3 Subunit - metabolism ; Fibromatosis, Aggressive - metabolism ; Down-Regulation ; Humans ; Gene Expression Regulation, Neoplastic ; Apoptosis - genetics ; Gene Expression Profiling - methods ; Mutation, Missense ; Adenomatous Polyposis Coli - pathology ; beta Catenin - metabolism ; beta Catenin - genetics ; Adenomatous Polyposis Coli - metabolism ; Abdominal Neoplasms - metabolism ; Fibromatosis, Aggressive - genetics ; Wnt Signaling Pathway - genetics ; Abdominal Neoplasms - genetics ; HEK293 Cells ; Cell Line, Tumor ; Core Binding Factor Alpha 3 Subunit - genetics ; Abdominal Neoplasms - pathology ; Adenomatous Polyposis Coli - genetics ; Fibromatosis, Aggressive - pathology ; Index Medicus
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