Journal
ONCOTARGET
Volume 8, Issue 24, Pages 39430-39442Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17049
Keywords
Wnt/beta-catenin; tumorigenicity; sphere formation; post-translational modification
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Funding
- Hong Kong Research Grants Council General Research Fund [775513]
- Research Grants Council Theme-based Research Scheme [T12-704116-R]
- SK Yee Medical Research Fund
- University Development Fund of The University of Hong Kong
- Small Project Fund of the University of Hong Kong [201409176136]
- Lee Shiu Family Foundation
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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 beta-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 (PP1C alpha) 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/PP1C alpha/ITCH axis sustains the dephosphorylation 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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