Prickle-1 Negatively Regulates Wnt/β-Catenin Pathway by Promoting Dishevelled Ubiquitination/Degradation in Liver Cancer

Background & Aims: Aberrant activation of Wnt signaling due to accumulation of β-catenin has been linked to tumorigenesis. Mutations of β-catenin, APC, and axins are important but not frequent enough to be accountable for the accumulation of β-catenin in human hepatocellular carcinoma (HCC). In this study, we characterized the roles of Prickle-1, a Dishevelled (Dvl)-associated protein, in regulation of Wnt/β-catenin activity in HCC. Methods: The expression levels of human Prickle-1 and Dvl3 were examined in HCC cell lines and human HCC samples. The interaction and effects of Prickle-1 on Dvl3, the Wnt/β-catenin pathway, and cell growth were assessed in HCC cell lines. Results: We showed that Prickle-1 bound with Dvl3 and facilitated Dvl3 ubiquitination/degradation, and this was through its destruction box (D-box) motifs. Enforced expression of Prickle-1 significantly reduced the Wnt/β-catenin activity and tumorigenic properties of HCC cells. Clinicopathologic analysis showed that underexpression of Prickle-1 was significantly associated with overexpression of Dvl3, β-catenin accumulation (P = .023), and larger tumor size (P = .030). Conclusions: Our results have elucidated a novel mechanistic relationship between Prickle-1 and Dvl3 in the Wnt/β-catenin pathway. The facilitation of Prickle-1 on Dvl3 degradation and the suppression of β-catenin activity and cell growth suggest that Prickle-1 is a negative regulator of the Wnt/β-catenin signaling pathway and is a putative tumor suppressor in human HCCs.