Exploring YAP1-centered networks linking dysfunctional CFTR to epithelial-mesenchymal transition

Mutations in the CFTR anion channel cause cystic fibrosis (CF) and have also been related to higher cancer incidence. Previously we proposed that this is linked to an emerging role of functional CFTR in protecting against epithelial-mesenchymal transition (EMT). However, the pathways bridging dysfunctional CFTR to EMT remain elusive. Here, we applied systems biology to address this question. Our data show that YAP1 is aberrantly active in the presence of mutant CFTR, interacting with F508del, but not with wt-CFTR, and that YAP1 knockdown rescues F508del-CFTR processing and function. Subsequent analysis of YAP1 interactors and roles in cells expressing either wt- or F508del-CFTR reveal that YAP1 is an important mediator of the fibrotic/EMT processes in CF. Alongside, five main pathways emerge here as key in linking mutant CFTR to EMT, namely, (1) the Hippo pathway; (2) the Wnt pathway; (3) the TGF beta pathway; (4) the p53 pathway; and (5) MYC signaling. Several potential hub proteins which mediate the crosstalk among these pathways were also identified, appearing as potential therapeutic targets for both CF and cancer.

Automated summary

In this study, systems biology was applied to investigate the pathways connecting dysfunctional CFTR to epithelial-mesenchymal transition (EMT). The results showed that YAP1 is abnormally active in the presence of mutant CFTR and interacts with F508del-CFTR, and YAP1 knockdown can rescue the processing and function of F508del-CFTR. Moreover, YAP1 was identified as an important mediator of the fibrotic/EMT processes in cystic fibrosis (CF). Additionally, several key pathways, including the Hippo pathway, the Wnt pathway, the TGF beta pathway, the p53 pathway, and MYC signaling, were found to be involved in linking mutant CFTR to EMT. The identification of potential hub proteins in these pathways may serve as therapeutic targets for both CF and cancer.