Hypoxia-induced EPHB2 promotes invasive potential of glioblastoma

EphB2, a receptor tyrosine kinase for ephrin ligands, is overexpressed in various cancers and plays an important role in tumor progression. EPHB2 promotes endothelial-mesenchymal transition (EMT) and elicits associated pathologic characteristics of glioblastoma multiforme (GBM) such as invasion and migration. However, the mechanisms of the EPHB2 regulatory network in glioma remain enigmatic. Here, we report that EPHB2 is epigenetically overexpressed in hypoxia, a condition highly prevalent in malignancy. Furthermore, HIF-2α is required for EPHB2 stabilization by hypoxia. Lastly, we discovered that the overexpression of EPHB2 promotes GBM invasion by the phosphorylation of paxillin in hypoxia. These findings establish the HIF-2α-EPHB2-paxillin axis as a regulatory mechanism of epithelial-mesenchymal transition.