| dc.description.abstract | Alterations of the Hippo-YAP pathway are potential targets for oral squamous cell carcinoma (OSCC) therapy, but heterogeneity in this pathway could be responsible for therapeutic resistance. The downstream effectors of this pathway, YAP/TAZ, are overexpressed in various cancers, including OSCC. However, the upstream regulators and their role in cancer progression remain unclear. Recent studies have revealed that Desmoglein-3 (DSG3) can regulate YAP, but on the other hand, YAP is also found to be able to influence DSG3 expression. Nevertheless, little is known about the role of this pathway in cell motility. This study analysed the Hippo-YAP signatures in a cohort of characterised keratinocyte cell lines derived from the mouth floor and buccal mucosa from different stages of OSCC tumour progression and focused on the specific role of YAP on invasive and metastatic potential. Heterogeneity of the Hippo-YAP pathway was detected in OSCC lines, including overexpression of YAP/TAZ and the major Hippo signalling components, as well as the variations in the genes encoding the intercellular anchoring junctional proteins, which could potentially regulate the Hippo pathway. Specifically, DSG3 exhibits a unique and mutually exclusive regulation of YAP via YAP phosphorylation during the collective migration of OSCC cells. Mechanistically, such regulation is associated with inhibition of phosphorylation of epidermal growth factor receptor (EGFR) (S695/Y1086) and its downstream effectors heat shock protein 27 (Hsp27) (S78/S82) and transcription factor AP-1 (c-Jun) (S63), leading to YAP inactivation via phosphorylation and cytoplasmic translocation. Additionally, OSCC lines display distinct phenotypes of YAP dependency or a mixed YAP and TAZ dependency for cell migration and present distinct patterns in YAP abundance and activity, with the latter being associated with YAP nuclear localisation. In conclusion, this study has provided evidence for a novel paradigm in the Hippo-YAP pathway and suggests a new regulation mechanism involved in the contact inhibition of cell locomotion in collective OSCC cell migration. | en_US |
