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Oncogene. 2014 Jun 12;33(24):3172-82. doi: 10.1038/onc.2013.279. Epub 2013 Jul 15.

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

Author information

1
Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
2
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
3
1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
4
Department of Pathology and Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
5
1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Graduate Institute of Clinical Medicine, National Cheng Kung University, Taipei, Taiwan.
6
1] Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan [2] Institute of Chemistry, Academia Sinica, Taipei, Taiwan [3] Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan.
7
1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA.
8
1] Department of Pathology, University of Michigan, Ann Arbor, MI, USA [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
9
1] Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan [2] Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
10
Graduate Institute of Clinical Medicine, National Cheng Kung University, Taipei, Taiwan.
11
1] Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan [2] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [3] Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan [4] NTU Center of Genomic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

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.

PMID:
23851495
PMCID:
PMC4096338
DOI:
10.1038/onc.2013.279
[Indexed for MEDLINE]
Free PMC Article
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