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.
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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)
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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
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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
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