Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha.

ABSTRACT: The hypoxia-inducible transcription factors (HIF) 1? and HIF-2? play a critical role in cellular response to hypoxia. Elevated HIF-? expression correlates with poor patient survival in a large number of cancers. Recent evidence suggests that HIF-2? appears to be preferentially expressed in neuronal tumor cells that exhibit cancer stem cell characteristics. These observations suggest that expression of HIF-1? and HIF-2? is differentially regulated in the hypoxic tumor microenvironment. However, the underlying mechanisms remain to be fully investigated. In this study, we investigated the transcriptional regulation of HIF-1? and HIF-2? under different physiologically relevant hypoxic conditions. We found that transcription of HIF-2? was consistently increased by hypoxia, whereas transcription of HIF-1? showed variable levels of repression. Mechanistically, differential regulation of HIF-? transcription involved hypoxia-induced changes in acetylation of core histones H3 and H4 associated with the proximal promoters of the HIF-1? or HIF-2? gene. We also found that, although highly stable under acute hypoxia, HIF-1? and HIF-2? proteins become destabilized under chronic hypoxia. Our results have thus provided new mechanistic insights into the differential regulation of HIF-1? and HIF-2? by the hypoxic tumor microenvironment. These findings also suggest an important role of HIF-2? in the regulation of tumor progression under chronic hypoxia.

SUBMITTER: Lin Q 

PROVIDER: S-EPMC3117969 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature