HIF-1α antagonizes p53-mediated apoptosis by triggering HIPK2 degradation

Many human diseases are characterized by the development of tissue hypoxia. Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration, such as angiogenesis, survival, and alterations in metabolism. The levels of HIF-1 alpha subunit are increased in most solid tumors not only by low oxygen but also by growth factors and oncogenes and correlate with patient prognosis and treatment failure. The link between HIF-1 alpha and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that HIF-1 alpha protects against drug-induced apoptosis by antagonizing the function of the tumor suppressor p53. HIF-1 alpha upregulation induced proteasomal degradation of homeodomain-interacting protein kinase-2 (HIPK2), the p53 apoptotic activator. Inhibition of HIF-1 alpha by siRNA, HIF-1 alpha-dominant negative or by zinc re-established the HIPK2 levels and the p53-mediated chemosensitivity in tumor cells. Our findings identify a novel circuitry between HIF-1 alpha and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies.