γ-Catenin acts as a tumor suppressor through context-dependent mechanisms in colorectal cancer

Purpose gamma-Catenin is a protein closely related to beta-catenin. While the overexpression of beta-catenin has been linked with impaired prognosis and survival in various malignancies, both oncogenic and tumor suppressor functions have been described for gamma-catenin. Thus, its role in cancer remains controversial. In this study, we examined the impact of gamma-catenin expression on the malignant potential of colorectal cancer cells. Methods gamma-Catenin was knocked down by short interfering RNA in the gamma-catenin-proficient DLD-1 cell line and stably overexpressed in the gamma-catenin-deficient cell line RKO. The effects of these molecular manipulations on the malignant potential of the cell lines were tested in vitro and in vivo in a xenograft tumor model. Results gamma-Catenin contributed to Wnt signaling independent of the cellular context. Unlike its sister molecule beta-catenin, gamma-catenin inhibited cellular invasion and anoikis in cells endogenously expressing gamma-catenin. In line with this tumor suppressor function, its de novo expression in RKO cells inhibited proliferation via cell cycle arrest. In a xenograft tumor model, overexpression of gamma-catenin starkly reduced tumor growth in vivo. Conclusions This is the first report demonstrating a tumor-suppressive effect of gamma-catenin in colorectal cancer both in vitro and in vivo. Detailed in vitro analysis revealed that effects of gamma-catenin differ in gamma-catenin proficient and deficient cells, indicating that its function in colorectal cancer is dependent on the cellular context. This finding adds to our understanding of gamma-catenin and may have implications for future studies of catenin/Wnt targeted cancer therapies.