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

Abstract

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.

• Authors: S-H Kao, W-L Wang, C-Y Chen, Y-L Chang, Y-Y Wu, Y-T Wang, S-P Wang, A I Nesvizhskii, Y-J Chen, T-M Hong, P-C Yang
• Journal: Oncogene (Oncogene) Vol. 33 Issue 24 Pg. 3172-82 (Jun 12 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 23851495 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• RNA, Messenger
• SNAI1 protein, human
• Snai2 protein, mouse
• Snail Family Transcription Factors
• Transcription Factors
• Ubiquitin
• STUB1 protein, human
• Ubiquitin-Protein Ligases
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Animals
• Blotting, Western
• Cadherins (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (metabolism, secondary)
• Cell Movement
• Cell Proliferation
• Cohort Studies
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Lung Neoplasms (metabolism, pathology)
• Mice
• Mice, Inbred NOD
• Mice, Nude
• Phosphorylation
• Proteolysis
• Proteomics
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Snail Family Transcription Factors
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Xenograft Model Antitumor Assays