Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers
Cancer-associated RNF43 mutations lead to activation of β-catenin signaling through aberrantly increasing Wnt-receptor levels at the membrane. Importantly, inactivating RNF43 mutations have been suggested to render cancer cells sensitive to Wnt-based therapeutics. However, the extent to which RNF43 mutations lead to impaired regulation of Wnt/β-catenin signaling has been poorly investigated. Here, we observed that tumors with a functional mismatch repair system show a predominant 5′-location of truncating RNF43 mutations, suggesting C-terminal truncations such as the most commonly reported p.G659fs mutation, do not affect β-catenin signaling. In accordance, expressing C-terminal truncation mutants and wild-type RNF43, showed equal effects on β-catenin signaling, Wnt-receptor turnover, and DVL-binding. We confirmed these observations at endogenous levels by CRISPR-Cas9-mediated knockout of G659fs RNF43 expression in KM12 cells and generating comparable mutations in HEK293T cells. We could not confirm previous reports linking RNF43 to p53 and E-cadherin breakdown. Our data also suggest that only colorectal cancer cells harboring N-terminal mutations of RNF43 convey Wnt-dependency onto the tumor cells. Results of this study have potentially important clinical implications indicating that Wnt-based therapeutics should be applied cautiously in cancer patients harboring RNF43 mutations.
|Persistent URL||dx.doi.org/10.1038/s41388-020-1232-5, hdl.handle.net/1765/125199|
|Journal||Oncogene: including Oncogene Reviews|
Li, S. (Shan), Lavrijsen, M. (Marla), Bakker, A. (Aron), Magierowski, M. (Marcin), Magierowska, K. (Katarzyna), Liu, P, … Smits, M.J.M. (2020). Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. Oncogene: including Oncogene Reviews. doi:10.1038/s41388-020-1232-5