GSK3β controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug.
Glycogen synthase kinase 3 beta (GSK3β) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial-mesenchymal transition (EMT). In this study, we find that the GSK3β-pSer9 level is associated with the expression of Slug ... in non-small cell lung cancer. GSK3β-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3β-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.
Mesh Terms:
Animals, Blotting, Western, Cadherins, Carcinoma, Non-Small-Cell Lung, Cell Movement, Cell Proliferation, Cohort Studies, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Glycogen Synthase Kinase 3, Humans, Immunoenzyme Techniques, Immunoprecipitation, Lung Neoplasms, Mice, Mice, Inbred NOD, Mice, Nude, Phosphorylation, Proteolysis, Proteomics, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Tumor Cells, Cultured, Ubiquitin, Ubiquitin-Protein Ligases, Xenograft Model Antitumor Assays
Animals, Blotting, Western, Cadherins, Carcinoma, Non-Small-Cell Lung, Cell Movement, Cell Proliferation, Cohort Studies, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Glycogen Synthase Kinase 3, Humans, Immunoenzyme Techniques, Immunoprecipitation, Lung Neoplasms, Mice, Mice, Inbred NOD, Mice, Nude, Phosphorylation, Proteolysis, Proteomics, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Tumor Cells, Cultured, Ubiquitin, Ubiquitin-Protein Ligases, Xenograft Model Antitumor Assays
Oncogene
Date: Jun. 12, 2014
PubMed ID: 23851495
View in: Pubmed Google Scholar
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