Hypoxia Inducible Factors regulate the p53 and notch pathways to promote cancer

Hypoxia Inducible Factors (HIFs) are αβ heterodimeric transcription factors that regulate important cellular processes, allowing both normal and cancerous cells to adapt to low oxygen conditions. Two central HIFα subunits, HIF1α and HIF2α, are highly expressed in many tumors and are correlated with poor patient prognosis. We therefore sought to further characterize their roles in cancer therapy responses and in tumorigenesis. While HIF1α promotes p53-dependent cell death in tumor cells, HIF2α has been suggested to regulate a subset of antioxidant enzymes, leading us to hypothesize that HIF2α may protect cells against Reactive Oxygen Species (ROS)-dependent damaging agents such as radiation. Herein we demonstrate that HIF2α inhibits the p53 pathway both in vitro and in Renal Clear Cell Carcinoma (ccRCC) patient samples, by limiting the amount of DNA damage incurred by the cell. HIF2α\u27s protective effect stems from its ability to maintain cellular redox balance, in the absence of which intracellular ROS increase and cells become much more sensitive to damage. Moreover, our novel p53 mutant mouse model suggests a novel role for HIF1α-mediated Notch stabilization in tumorigenesis. Indeed, HIF1α heterozygosity led to a significant reduction in the incidence of thymic lymphomas strongly associated with impaired Notch pathway activity. Both studies elucidate mechanisms whereby the HIFα subunits impact directly on tumor biology and provide strong evidence in support of the development of specific HIF inhibitors for use in cancer therapy