Molecular mechanisms of oxygen sensing in malignant brain tumours: pro- and antitumourigenic effects

Regions of low oxygen tension are common findings in malignant tumors being associated with increased frequency of tumor invasion and metastasis. Indeed, the ability to initiate homeostatic responses and adapt to hypoxia, e.g. by induction of angiogenesis, represents an important and crucial aspect in solid tumor growth. A significant advance in our understanding of the hypoxia response stems from the discovery of the hypoxia inducible transcription factor HIF-1á and HIF-2á which act as key regulators of hypoxia-induced gene expression. Interestingly, however, the HIF pathway is known to encompass tumor growth promoting as well as inhibiting effects. As we could recently show, the choice between these opposite responses critically depends on HIF protein levels. Thus, high-level HIF expression induces a qualitative switch in the cellular response to tumor-suppressive actions.

HIF activity is exquisitely controlled by HIF prolyl-hydroxylase (PHD) comprising four orthologues. We further characterized localization, function and specificity of the different PHD orthologues in oxygen dependent control of HIF in glioblastomas using gain and loss-of-function experiments. Interestingly, we identified mediated PHD2/3 as potential HIF target genes. Despite the need for oxygen all PHD orthologues retained activity under low oxygen tension and efficiently suppressed HIF-1á/HIF-2á protein accumulation and target gene expression. Given the dual role of HIF in regulating cell survival and cell death tight regulation of HIF levels is essential for tumor survival and growth. The PHD enzymes may represent a crucial system that functions as a negative feedback mechanism under low oxygen concentrations preventing HIF-á levels from reaching toxic concentrations.