Chronic hypoxia‐induced slug promotes invasive behavior of prostate cancer cells by activating expression of ephrin‐B1

Advanced solid tumors are exposed to hypoxic conditions over longer periods of time as they grow. Tumor hypoxia is a major factor that induces malignant progression, but most previous studies on tumor hypoxia were performed under short‐term hypoxia for up to 72 hours and few studies have focused on tumor response to chronic hypoxic conditions. Here we show a molecular mechanism by which chronic hypoxia promotes invasive behavior in prostate cancer cells. We found that an epithelial‐mesenchymal transition (EMT)‐driving transcription factor, slug, is specifically upregulated under chronic hypoxia and promotes tumor cell migration and invasion. Unexpectedly, processes associated with EMT, such as loss of E‐cadherin, are not observed under chronic hypoxia. Instead, expression of ephrin‐B1, a ligand of Eph‐related receptor tyrosine kinases, is markedly induced by slug through E‐box motifs and promotes cell migration and invasion. Furthermore, slug and ephrin‐B1 are highly coexpressed in chronic hypoxic cells of human prostate adenocarcinoma tissues after androgen deprivation, which is known to cause tumor hypoxia. Taken together, these results indicate that chronic hypoxia‐induced slug promotes invasive behavior of prostate cancer cells by activating the expression of ephrin‐B1. In addition, ephrin‐B1 may be a novel therapeutic target in combination with androgen deprivation therapy for aggressive prostate cancer.