GSK3β controls epithelial–mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug

• Published in: Oncogene Vol. 33; no. 24; pp. 3172 - 3182
• Main Authors: Kao, S-H, Wang, W-L, Chen, C-Y, Chang, Y-L, Wu, Y-Y, Wang, Y-T, Wang, S-P, Nesvizhskii, A I, Chen, Y-J, Hong, T-M, Yang, P-C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-06-2014; Nature Publishing Group
• Subjects: 631/67/1612/1350; 631/67/322; 631/80/458; 631/80/84/2176; Animals; Apoptosis; Blotting, Western; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - secondary; Care and treatment; Cell Biology; Cell migration; Cell Movement; Cell Proliferation; Cellular signal transduction; Cohort Studies; E-cadherin; Epithelial-Mesenchymal Transition; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hsc70 protein; Human Genetics; Humans; Immunoenzyme Techniques; Immunoprecipitation; Internal Medicine; Kinases; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, Nude; Non-small cell lung carcinoma; Oncology; original-article; Patient outcomes; Phosphorylation; Physiological aspects; Protein turnover; Proteins; Proteolysis; Proteomics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Small cell lung carcinoma; Snail Family Transcription Factors; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Cells, Cultured; Tumors; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Xenograft Model Antitumor Assays; Zinc finger proteins; GSK3β; CHIP; post-translational modification; Slug
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.279

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.