Loss of junctional plakoglobin (JUP) activates PI3K/AKT signaling in head and neck squamous cell carcinoma

Head and neck squamous cell carcinomas (HNSCC) are characterized by poor prognosis, primarily due to early metastatic spread. The junctional plaque protein plakoglobin (JUP), a key desmosomal component, contributes not only to cell-cell adhesion but also to intracellular signaling processes that regulate proliferation, migration, and metastasis. Although JUP has been implicated in tumor progression in other cancer types, its role in HNSCC remains largely undefined. In this study, clinical data from The Cancer Genome Atlas (TCGA) were analyzed to determine the prognostic relevance of JUP expression in HNSCC. Functional studies were performed in HPV-negative (FaDu) and HPV-positive (UPCI-SCC-154) cells following siRNA-mediated JUP knockdown, assessing proliferation, wound healing, and signaling activity. Pharmacological inhibition experiments were conducted to evaluate pathway specificity. Low JUP expression was significantly associated with advanced metastatic stage and reduced overall survival in HNSCC patients. In vitro, JUP-deficient cells exhibited accelerated wound closure and increased proliferation. Mechanistically, loss of JUP led to activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, and the enhanced motility phenotype could be reversed by pharmacological PI3K inhibition. Taken together, these findings identify plakoglobin as a negative regulator of PI3K signaling in HNSCC. Loss of JUP promotes tumor cell motility and proliferation, underscoring its potential value as a prognostic biomarker and therapeutic target in head and neck cancer.