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Article: Dishevelled-3 phosphorylation is governed by HIPK2/PP1Cα/ITCH axis and the non-phosphorylated form promotes cancer stemness via LGR5 in hepatocellular carcinoma

TitleDishevelled-3 phosphorylation is governed by HIPK2/PP1Cα/ITCH axis and the non-phosphorylated form promotes cancer stemness via LGR5 in hepatocellular carcinoma
Authors
KeywordsPost-translational modification
Sphere formation
Tumorigenicity
Wnt/β-catenin
Issue Date2017
PublisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html
Citation
Oncotarget, 2017, v. 8 n. 24, p. 39430-39442 How to Cite?
AbstractDishevelled-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.
Persistent Identifierhttp://hdl.handle.net/10722/244250
ISSN
2015 Impact Factor: 5.008
2015 SCImago Journal Rankings: 2.294
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTsui, YM-
dc.contributor.authorSze, MF-
dc.contributor.authorTung, KK-
dc.contributor.authorHo, DWH-
dc.contributor.authorLee, KW-
dc.contributor.authorNg, IOL-
dc.date.accessioned2017-08-31T08:56:28Z-
dc.date.available2017-08-31T08:56:28Z-
dc.date.issued2017-
dc.identifier.citationOncotarget, 2017, v. 8 n. 24, p. 39430-39442-
dc.identifier.issn1949-2553-
dc.identifier.urihttp://hdl.handle.net/10722/244250-
dc.description.abstractDishevelled-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.-
dc.languageeng-
dc.publisherImpact Journals LLC. The Journal's web site is located at http://www.impactjournals.com/oncotarget/index.html-
dc.relation.ispartofOncotarget-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectPost-translational modification-
dc.subjectSphere formation-
dc.subjectTumorigenicity-
dc.subjectWnt/β-catenin-
dc.titleDishevelled-3 phosphorylation is governed by HIPK2/PP1Cα/ITCH axis and the non-phosphorylated form promotes cancer stemness via LGR5 in hepatocellular carcinoma-
dc.typeArticle-
dc.identifier.emailTsui, YM: ymtsui@hku.hk-
dc.identifier.emailSze, MF: karensze@hkucc.hku.hk-
dc.identifier.emailHo, DWH: dwhho@hku.hk-
dc.identifier.emailNg, IOL: iolng@hku.hk-
dc.identifier.authorityHo, DWH=rp02285-
dc.identifier.authorityLee, KW=rp00447-
dc.identifier.authorityNg, IOL=rp00335-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.18632/oncotarget.17049-
dc.identifier.pmcidPMC5503623-
dc.identifier.scopuseid_2-s2.0-85020627624-
dc.identifier.hkuros276926-
dc.identifier.volume8-
dc.identifier.issue24-
dc.identifier.spage39430-
dc.identifier.epage39442-
dc.identifier.eissn1949-2553-
dc.identifier.isiWOS:000403311900112-
dc.publisher.placeUnited States-
dc.customcontrol.immutablecsl 171020-

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