title: Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair.
abstract: The epithelium of asthmatics is characterized by reduced expression of E-cadherin and increased expression of the basal cell markers ck-5 and p63 that is indicative of a relatively undifferentiated repairing epithelium. This phenotype correlates with increased proliferation, compromised wound healing and an enhanced capacity to undergo epithelial-mesenchymal transition (EMT). The transcription factor β-catenin plays a vital role in epithelial cell differentiation and regeneration, depending on the co-factor recruited. Transcriptional programs driven by the β-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the β-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the β-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGFβ1 in the presence or absence of the selective small molecule ICG-001 to inhibit β-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, β-catenin, fibronectin and ITGβ1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGFβ1 induced EMT, characterized by reduced E-cadherin expression with increased expression of α-smooth muscle actin and EDA-fibronectin. Either co-treatment or therapeutic administration of ICG-001 completely inhibited TGFβ1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGFβ1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITGβ1 and fibronectin expression. These data support our hypothesis that modulating the β-catenin/CBP signaling axis plays a key role in epithelial plasticity and function.
authors: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia. Electronic address: fatemeh.moheimani@newcastle.edu.au.
authors: Fatemeh
authors: F
authors: Moheimani
authors: UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors: Hollis M
authors: HM
authors: Roth
authors: UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors: Jennifer
authors: J
authors: Cross
authors: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
authors: Andrew T
authors: AT
authors: Reid
authors: UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors: Furquan
authors: F
authors: Shaheen
authors: UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors: Stephanie M
authors: SM
authors: Warner
authors: UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors: Jeremy A
authors: JA
authors: Hirota
authors: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada; Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands 6009, Western Australia, Australia; Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth 6001, Western Australia, Australia; School of Paediatrics and Child Health, Centre for Health Research, The University of Western Australia, Nedlands, Australia; Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Nedlands 6009, Western Australia, Australia.
authors: Anthony
authors: A
authors: Kicic
authors: Department of Medicine, Division of Pulmonary and Critical Care, University of Washington, Seattle, WA, USA.
authors: Teal S
authors: TS
authors: Hallstrand
authors: Norris Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, and Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, CA, USA.
authors: Michael
authors: M
authors: Kahn
authors: Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands 6009, Western Australia, Australia; Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth 6001, Western Australia, Australia; School of Paediatrics and Child Health, Centre for Health Research, The University of Western Australia, Nedlands, Australia; Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Nedlands 6009, Western Australia, Australia.
authors: Stephen M
authors: SM
authors: Stick
authors: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
authors: Philip M
authors: PM
authors: Hansbro
authors: UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
authors: Tillie-Louise
authors: TL
authors: Hackett
authors: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada. Electronic address: Darryl.Knight@newcastle.edu.au.
authors: Darryl A
authors: DA
authors: Knight
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D011744:Pyrimidinones / Q000494:pharmacology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012795:Sialoglycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C495270:CTNNB1 protein, human; D005353:Fibronectins; C492448:ICG 001; D053539:Keratin-19; D053555:Keratin-5; D010446:Peptide Fragments; D011744:Pyrimidinones; D012795:Sialoglycoproteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; C571744:bone sialoprotein (35-62), human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: Airway epithelium; Epithelial–mesenchymal transition; ICG-001; Wound repair; β-Catenin/CBP