?-catenin S45F mutation results in apoptotic resistance.

ABSTRACT: Wnt/?-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 ?-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of ?-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in ?-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 ?-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 ?-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/?-catenin signaling induced by this mutation.

SUBMITTER: Braggio D 

PROVIDER: S-EPMC7441052 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature