TEAD4 Overexpression Promotes Epithelial-Mesenchymal Transition and Associates with Aggressiveness and Adverse Prognosis in Head Neck Squamous Cell Carcinoma

BACKGROUND:Deregulated Hippo signaling has been uncovered to be intricately involved in tumorigenesis. Transcriptional factor TEADs serve as key mediators of Hippo signaling and have been increasingly appreciated as putative oncogenes driving cancer initiation and progression. However, its expression pattern and oncogenic role of TEAD4 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. METHODS:TEAD4 mRNA expression in HNSCC was determined by data mining and analyses from TCGA dataset and four independent cohorts with transcriptional profiling data publically available. The protein abundance of TEAD4 was measured by immunohistochemistry in 105 primary HNSCC samples and associations between its expression and clinicopathological parameters and patient survival were evaluated. The oncogenic roles of TEAD4 was further determined by 4-nitroquinoline 1-oxide (4NQO)-induced animal model, both knockdown/overexpression assay and TGF-β1-induced epithelia-mesenchymal transition (EMT) in vitro. RESULTS:Both mRNA and protein abundance of TEAD4 were significantly increased in HNSCC as compared to its non-tumor counterparts. Overexpression of TEAD4 significantly associated with high pathological grade, cervical node metastasis, advanced clinical stage and reduced overall and disease-free survival. In the 4NQO-induced HNSCC mouse model, increased TEAD4 immunostaining was found associated with disease progression. TEAD4 knockdown significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in HNSCC cells, while its overexpression resulted in opposite effects and EMT. Moreover, TEAD4 was critically involved in TGF-β1-induced EMT in HNSCC cells. CONCLUSIONS:Our findings reveal that TEAD4 serves as a novel prognostic biomarker and putative oncogene for HNSCC by promoting cell proliferation, migration and invasion, and EMT.