NDRG1 promotes growth of hepatocellular carcinoma cells by directly interacting with GSK-3β and Nur77 to prevent β-catenin degradation.
The N-myc downstream regulated gene 1 (NDRG1) is significantly associated with advanced tumor stages and poor survival of hepatocellular carcinoma (HCC), thereby implicating it as a potential target for HCC treatment. We aim to further understand its biological roles in hepatocarcinogenesis, as a means to exploit it for therapeutic purposes. ... By screening using the ProtoArray® Human Protein Microarrays, we identified glycogen synthase kinase 3β (GSK-3β) and the orphan nuclear receptor (Nur77) as potential interaction partners of NDRG1. These interactions were confirmed in HCC cell lines in vitro by co-immunoprecipitation; and co-localizations of NDRG1 with GSK-3β and Nur77 were observed by immunofluorescence staining. Additionally, high levels of NDRG1 competitively bind to GSK-3β and Nur77 to allow β-catenin to escape degradation, with consequent elevated levels of downstream oncogenic genes. In vivo, we consistently observed that NDRG1 suppression in HCC xenografts decreased β-catenin levels and its downstream target Cyclin D1, with concomitant tumor growth inhibition. Clinically, the over-expression of NDRG1 in HCC patient samples is positively correlated with GSK-3β-9ser (|”‚ R | = 0.28, p = 0.01), Nur77 (|”‚ R | = 0.42, p < 0.001), and β-catenin (| R |= 0.32, p = 0.003) expressions. In conclusion, we identified GSK-3β and Nur77 as novel interaction partners of NDRG1. These protein-protein interactions regulate the turnover of β-catenin and subsequent downstream signaling mediated by β-catenin in HCC cells, and provides potential targets for future therapeutic interventions.
Mesh Terms:
Animals, Antineoplastic Agents, Carcinoma, Hepatocellular, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Doxycycline, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hep G2 Cells, Humans, Immunoblotting, Intracellular Signaling Peptides and Proteins, Liver Neoplasms, Mice, Nude, Microscopy, Fluorescence, Niacinamide, Nuclear Receptor Subfamily 4, Group A, Member 1, Phenylurea Compounds, Protein Binding, Proteolysis, RNA Interference, Tumor Burden, Xenograft Model Antitumor Assays, beta Catenin
Animals, Antineoplastic Agents, Carcinoma, Hepatocellular, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Doxycycline, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hep G2 Cells, Humans, Immunoblotting, Intracellular Signaling Peptides and Proteins, Liver Neoplasms, Mice, Nude, Microscopy, Fluorescence, Niacinamide, Nuclear Receptor Subfamily 4, Group A, Member 1, Phenylurea Compounds, Protein Binding, Proteolysis, RNA Interference, Tumor Burden, Xenograft Model Antitumor Assays, beta Catenin
Oncotarget
Date: Oct. 06, 2015
PubMed ID: 26359353
View in: Pubmed Google Scholar
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