Hypoxia and Tumorigenesis

Basic Sciences

Investigators

Linked publications & trials

Abstract

Hypoxia (deficiency in oxygen supply) is tightly associated with tumorigenesis and angiogenesis, as well as with cerebral and myocardial ischemia. When challenged by low oxygen tension, cells activate hypoxia-inducible factor 1 (HIF-1), a master regulator of oxygen homeostasis, bringing about transcriptional up-regulation of a variety of hypoxia-responsive genes, including vascular endothelial growth factor, nitric oxide synthases, glucose transporters, and glycolytic enzymes. HIF-1 is a heterodimeric transcription factor, composed of HIF-1a and HIF-1b of the basic helix-loop-helix PAS family. Our research focuses on the molecular mechanisms underlying HIF-1 activation, the role of HIF-1a in tumorigenesis, and the molecular basis for therapeutic drug targeting. Previously, we and others demonstrated that HIF-1 activation is regulated primarily by posttranslational modifications of HIF-1a, resulting in increased protein stability and transcriptional activity. The HIF-1a level is controlled by oxygen-dependent proteolysis via the ubiquitin-proteasome pathway that targets the oxygen-dependent degradation domain (ODD) of HIF-1a. The HIF-1a E3 ubiquitin ligase contains the tumor suppressor von Hippel-Lindau (VHL) protein, which binds ODD and catalyzes polyubiquitination of HIF-1a. The VHL protein interacts with HIF-1a via a specific recognition of hydroxylated Pro402 or Pro564, both of which are modified in normoxia by a family of prolyl-4-hydroxylases functioning as oxygen sensors. To gain insights into the molecular determinant of prolyl hydroxylation, we recently identified a leucine residue (Leu-574) downstream of Pro-564 to be crucial for the VHL-mediated degradation of HIF-1a. Moreover, we have demonstrated that the leucine residue is required for recruiting a key HIF prolyl-4-hydrxylase. Thus, the identification of Leu-574 may provide a molecular basis for drug targeting of HIF-1a activity. Although hypoxia induces an increase in HIF-1a levels, what is equally interesting is why HIF-1a is constitutively degraded. We are in the process of identifying novel functions and regulatory mechanisms of HIF-1a. Solid tumors contain hypoxic regions that often acquire diminished apoptotic potential and resistance to chemo- or radio-therapy. Hypoxia may induce mutations of critical genes, ultimately resulting in genomic instability. The role of HIF-1a in tumorigenesis has been implicated by the heightened expression of HIF-1a and HIF-2a, a close member of the family, and by the correlation of their overexpression with poor diagnosis. Experimental evidence have shown that HIF-1a is required for tumor angiogenesis and hypoxia-induced growth arrest as well. By taking advantage of the HIF-1a variants with defined biochemical activities, we are making progress of characterizing the role of HIF-1a in tumorigenesis, and elucidating the molecular mechanisms underlying hypoxic effects on tumor development. Novel hypotheses have been generated from the study, possibly leading to the invention of new therapeutic drug targets.