Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 131; no. 4; p. 1218
• Main Authors: Chan, David W, Chan, Chung-Yiu, Yam, Judy W P, Ching, Yick-Pang, Ng, Irene O L
• Format: Journal Article
• Language: English
• Published: United States 01.10.2006
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; beta Catenin - metabolism; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - physiopathology; Cell Division - physiology; Cell Line; Consensus Sequence; Dishevelled Proteins; Gene Expression Regulation, Neoplastic; Humans; Kidney - cytology; LIM Domain Proteins; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - physiopathology; Molecular Sequence Data; Phosphoproteins - genetics; Phosphoproteins - metabolism; Signal Transduction - physiology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin - metabolism; Wnt Proteins - metabolism
• ISSN: 0016-5085
• DOI: 10.1053/j.gastro.2006.07.020

Aberrant activation of Wnt signaling due to accumulation of beta-catenin has been linked to tumorigenesis. Mutations of beta-catenin, APC, and axins are important but not frequent enough to be accountable for the accumulation of beta-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/beta-catenin activity in HCC. 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/beta-catenin pathway, and cell growth were assessed in HCC cell lines. 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/beta-catenin activity and tumorigenic properties of HCC cells. Clinicopathologic analysis showed that underexpression of Prickle-1 was significantly associated with overexpression of Dvl3, beta-catenin accumulation (P = .023), and larger tumor size (P = .030). Our results have elucidated a novel mechanistic relationship between Prickle-1 and Dvl3 in the Wnt/beta-catenin pathway. The facilitation of Prickle-1 on Dvl3 degradation and the suppression of beta-catenin activity and cell growth suggest that Prickle-1 is a negative regulator of the Wnt/beta-catenin signaling pathway and is a putative tumor suppressor in human HCCs.