Dishevelled-3 phosphorylation is governed by HIPK2/PP1Cα/ITCH axis and the non-phosphorylated form promotes cancer stemness via LGR5 in hepatocellular carcinoma
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Yu-Man Tsui1,2, Karen Man-Fong Sze1,2, Edmund Kwok-Kwan Tung1,2, Daniel Wai-Hung Ho1,2, Terence Kin-Wah Lee1,2,3 and Irene Oi-Lin Ng1,2
1State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong
2Department of Pathology, The University of Hong Kong, Hong Kong
3Present address: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
Irene Oi-Lin Ng, email: [email protected]
Keywords: Wnt/β-catenin, tumorigenicity, sphere formation, post-translational modification
Received: October 05, 2016 Accepted: March 20, 2017 Published: April 11, 2017
Dishevelled-3 (Dvl3) is regarded as a binding hub with many different interacting partners. However, its regulation and mechanism on cancer stemness remain to be explored. In this study, we showed that Dvl3 was significantly overexpressed in human hepatocellular carcinomas (HCCs) and promoted cancer stemness both in vitro and in vivo. We found that the non-phosphorylated (NP)-Dvl3 was more stable than the phosphorylated form, more active in activating β-catenin transcriptional activity, and more potent in enhancing self-renewal ability in HCC cells. Mechanistically, we confirmed that the homeodomain-interacting protein kinase-2 (HIPK2) and E3 ubiquitin ligase ITCH were able to physically bind to Dvl3 protein. Knockdown of HIPK2 and the protein phosphatase regulatory unit C-alpha (PP1Cα) resulted in sustained Dvl3 phosphorylation and hence decrease in the NP form of Dvl3. On the other hand, knockdown of E3 ubiquitin ligase ITCH reduced the phosphorylation-induced degradation and stabilized the phosphorylated Dvl3 protein. Furthermore, the NP-Dvl3 enhanced the LGR5 promoter activity to upregulate LGR5 expression, which was associated with increased cancer stemness in HCC. Our findings established that HIPK2/PP1Cα/ITCH axis sustains the de-phosphorylation of Dvl3. This post-translational modification of Dvl3 in turn maintains LGR5 expression and enhances the cancer stemness properties in HCC.
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