title: 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.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kao
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: W-L
authors.initials: WL
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Pathology and Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chang
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Graduate Institute of Clinical Medicine, National Cheng Kung University, Taipei, Taiwan.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Wang
authors.affiliation: 1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY, USA.
authors.forename: S-P
authors.initials: SP
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: A I
authors.initials: AI
authors.lastname: Nesvizhskii
authors.affiliation: 1] Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan [2] Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, National Cheng Kung University, Taipei, Taiwan.
authors.forename: T-M
authors.initials: TM
authors.lastname: Hong
authors.affiliation: 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.
authors.forename: P-C
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000556:secondary*; D002465:Cell Movement; D049109:Cell Proliferation; D015331:Cohort Studies; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D010766:Phosphorylation; D059748:Proteolysis; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D025801:Ubiquitin; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3