Abstract 2053: Differential regulation of hypoxia-inducible factors 1α and 2α by hypoxia

Abstract

Abstract The hypoxia-inducible transcription factors (HIF)-1α and -2α are the key transcription factors regulating the expression of hypoxia-induced genes critical for a wide range of tumor cell functions from survival to clonal selection to metastasis. 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. Furthermore, elevated HIF-2α expression is co-localized in vivo with expression of neural crest progenitor markers, suggesting a preferential association of HIF-2α expression with the immature stem cell-like neuroblastoma cells. These observations suggest that expression of HIF-1α and -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 HIF-1α and -2α under different hypoxic conditions. In addition to conventional hypoxia treatment, we developed an adaptive chronic hypoxia approach by preconditioning tumor cells at 5% O2 before reducing pO2 to hypoxia levels (below 2% O2) to mimic in vivo tumor hypoxia. We found that transcription of HIF-2α was consistently increased by hypoxia in a panel of neuroblastoma cell lines, whereas transcription of HIF-1α showed variable levels of repression. Mechanistically, differential regulation of HIF-α transcription involved hypoxia-induced changes in actetylation 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 expression and localization of HIF-1α and -2α proteins within the hypoxic tumor microenvironment. These findings further underscore the importance of HIF-2α in the regulation of tumor progression, especially in the regulation of the stem cell-like tumor cell population as observed in neuronal tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2053. doi:10.1158/1538-7445.AM2011-2053