Differential hypoxic regulation of hypoxia-inducible factors 1α and 2α

Q Lin, X Cong, Z Yun - Molecular Cancer Research, 2011 - AACR
Q Lin, X Cong, Z Yun
Molecular Cancer Research, 2011AACR
The hypoxia-inducible transcription factors (HIF) 1α and HIF-2α play a critical role in cellular
response to hypoxia. Elevated HIF-α expression correlates with poor patient survival in a
large number of cancers. Recent evidence suggests that HIF-2α appears to be preferentially
expressed in neuronal tumor cells that exhibit cancer stem cell characteristics. These
observations suggest that expression of HIF-1α and HIF-2α is differentially regulated in the
hypoxic tumor microenvironment. However, the underlying mechanisms remain to be fully …
Abstract
The hypoxia-inducible transcription factors (HIF) 1α and HIF-2α play a critical role in cellular response to hypoxia. Elevated HIF-α expression correlates with poor patient survival in a large number of cancers. Recent evidence suggests that HIF-2α appears to be preferentially expressed in neuronal tumor cells that exhibit cancer stem cell characteristics. These observations suggest that expression of HIF-1α and HIF-2α 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- and HIF- under different physiologically relevant hypoxic conditions. We found that transcription of HIF- was consistently increased by hypoxia, whereas transcription of HIF- showed variable levels of repression. Mechanistically, differential regulation of HIF-α transcription involved hypoxia-induced changes in acetylation of core histones H3 and H4 associated with the proximal promoters of the HIF- or HIF- gene. We also found that, although highly stable under acute hypoxia, HIF-1α and HIF-2α proteins become destabilized under chronic hypoxia. Our results have thus provided new mechanistic insights into the differential regulation of HIF- and HIF- by the hypoxic tumor microenvironment. These findings also suggest an important role of HIF-2α in the regulation of tumor progression under chronic hypoxia. Mol Cancer Res; 9(6); 757–65. ©2011 AACR.
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