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. EPHB2 is epigenetically overexpressed in hypoxia, a condition highly prevalent in malignancy. Furthermore, HIF-2α is required for EPHB2 stabilization by hypoxia.