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

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

doi:10.1038/onc.2013.279

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

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

Authors

S-H Kao¹, W-L Wang², C-Y Chen³, Y-L Chang⁴, Y-Y Wu⁵, Y-T Wang⁶, S-P Wang⁷, A I Nesvizhskii⁸, Y-J Chen⁹, T-M Hong¹⁰, P-C Yang¹¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Cadherins / genetics
Cadherins / metabolism*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / secondary*
Cell Movement
Cell Proliferation
Cohort Studies
Epithelial-Mesenchymal Transition*
Gene Expression Regulation, Neoplastic
Glycogen Synthase Kinase 3 / genetics
Glycogen Synthase Kinase 3 / metabolism*
Glycogen Synthase Kinase 3 beta
Humans
Immunoenzyme Techniques
Immunoprecipitation
Lung Neoplasms / metabolism
Lung Neoplasms / 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
Transcription Factors / metabolism*
Tumor Cells, Cultured
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Xenograft Model Antitumor Assays

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding