title: Differential hypoxic regulation of hypoxia-inducible factors 1alpha and 2alpha.
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-1α and HIF-2α under different physiologically relevant hypoxic conditions. We found that transcription of HIF-2α was consistently increased by hypoxia, whereas transcription of HIF-1α 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-1α or HIF-2α 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-1α and HIF-2α by the hypoxic tumor microenvironment. These findings also suggest an important role of HIF-2α in the regulation of tumor progression under chronic hypoxia.
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, P. O. Box 208040, New Haven, CT 06520-8040, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lin
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Cong
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yun
mesh_terms: D000107:Acetylation; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D015687:Cell Hypoxia / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D059016:Tumor Microenvironment / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1