Heterogeneity in binding and gene-expression regulation by HIF-2α

Here, we demonstrate by chromatin immunoprecipitation that the binding of hypoxia-inducible factors to gene regulatory regions is differentially influenced in cancer cells. Binding of HIF-2α varies depending on hypoxic conditions, although HIF-1α is constantly bound to these regions. We found by RNA interference experiments that HIF-2α plays a minor role in VEGF gene upregulation under hypoxia or CoCl2 treatment, even when both HIFs are similarly bound to the promoter region. HIF-2α activated or suppressed the ENO1 gene under various conditions, irrespective of promoter binding. We additionally found that HIF dependence on EPO gene induction could be altered depending on the conditions, irrespective of the binding pattern of HIFs. These results demonstrate that, unlike HIF-1α, HIF-2α differentially binds and regulates transcription under hypoxia.