Disruption of β-catenin/CBP signaling inhibits human airway epithelial-mesenchymal transition and repair

The epithelium of asthmatics is characterized by reduced expression of beta-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 pcatenin plays a vital role in epithelial cell differentiation and regeneration, depending on the alpha-factor recruited. Transcriptional programs driven by the beta-catenin/CBP axis are critical for maintaining an undifferentiated and proliferative state, whereas the beta-catenin/p300 axis is associated with cell differentiation. We hypothesized that disrupting the beta-catenin/CBP signaling axis would promote epithelial differentiation and inhibit EMT. We treated monolayer cultures of human airway epithelial cells with TGF beta 1 in the presence or absence of the selective small molecule ICG-001 to inhibit beta-catenin/CBP signaling. We used western blots to assess expression of an EMT signature, CBP, p300, beta-catenin, fibronectin and ITG beta 1 and scratch wound assays to assess epithelial cell migration. Snai-1 and -2 expressions were determined using q-PCR. Exposure to TGF beta 1 induced EMT, characterized by reduced E-cadherin expression with increased expression of ot-smooth muscle actin and EDA-fibronectin. Either alpha-treatment or therapeutic administration of ICG-001 completely inhibited TGF beta 1-induced EMT. ICG-001 also reduced the expression of ck-5 and -19 independent of TGF beta 1. Exposure to ICG-001 significantly inhibited epithelial cell proliferation and migration, coincident with a down regulation of ITG beta 1 and fibronectin expression. These data support our hypothesis that modulating the beta-catenin/CBP signaling axis plays a key role in epithelial plasticity and function. (C) 2015 Elsevier Ltd. All rights reserved.