The NOTCH4-HEY1 pathway induces epithelial mesenchymal transition in head and neck squamous cell carcinoma

Background: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood. Methods: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell cycle assays. We also compared the relationships among NOTCH4, HEY1 and epithelial mesenchymal transition (EMT) related genes using the TCGA data set and in vitro assays. Results: HEY1 is specifically up-regulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison to other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell cycle dysregulation. Furthermore, NOTCH4 and HEY1 up-regulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression were associated with an EMT phenotypes as well as increased invasion and cell migration. Conclusion: In HNSCC the NOTCH4-HEY1 pathway is specifically up-regulated, induces proliferation and cisplatin resistance, and promotes EMT.

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