Dishevelled-3 phosphorylation is governed by HIPK2/PP1Cα/ITCH axis and the non-phosphorylated form promotes cancer stemness via LGR5 in hepatocellular carcinoma
| العنوان: | 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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| المؤلفون: | Edmund Kwok-Kwan Tung, Yu-Man Tsui, Karen Man-Fong Sze, Terence Kin Wah Lee, Daniel W.H. Ho, Irene Oi-Lin Ng |
| المصدر: | Oncotarget |
| بيانات النشر: | Impact Journals LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, sphere formation, Dishevelled Proteins, Gene Expression, Receptors, G-Protein-Coupled, Mice, 0302 clinical medicine, Protein Phosphatase 1, Tumor Cells, Cultured, Medicine, Phosphorylation, chemistry.chemical_classification, Gene knockdown, Wnt/β-catenin, biology, Protein Stability, Liver Neoplasms, Wnt signaling pathway, Middle Aged, Dishevelled, Ubiquitin ligase, Oncology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, Signal transduction, Research Paper, Protein Binding, Signal Transduction, Adult, Carcinoma, Hepatocellular, Ubiquitin-Protein Ligases, Protein Serine-Threonine Kinases, Models, Biological, 03 medical and health sciences, Cell Line, Tumor, Animals, Humans, Aged, business.industry, Cancer, Protein phosphatase 1, medicine.disease, Repressor Proteins, Disease Models, Animal, 030104 developmental biology, chemistry, post-translational modification, Immunology, biology.protein, Cancer research, tumorigenicity, business, Carrier Proteins |
| الوصف: | 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. published_or_final_version |
| اللغة: | English |
| تدمد: | 1949-2553 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::90204d510d6b56ec2bbe3a312bf1843bTest http://europepmc.org/articles/PMC5503623Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....90204d510d6b56ec2bbe3a312bf1843b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19492553 |
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