HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase

Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration. HIFα protein levels are increased in most solid tumours and correlate with patient prognosis. The link between HIF and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that Caenorhabditis elegans HIF-1 protects against DNA-damage-induced germ cell apoptosis by antagonizing the function of CEP-1, the homologue of the tumour suppressor p53. The antiapoptotic property of HIF-1 is mediated by means of transcriptional upregulation of the tyrosinase family member TYR-2 in the ASJ sensory neurons. TYR-2 is secreted by ASJ sensory neurons to antagonize CEP-1-dependent germline apoptosis. Knock down of the TYR-2 homologue TRP2 (also called DCT) in human melanoma cells similarly increases apoptosis, indicating an evolutionarily conserved function. Our findings identify a novel link between hypoxia and programmed cell death, and provide a paradigm for HIF-1 dictating apoptotic cell fate at a distance. Living cells have evolved a sophisticated response mechanism to help them survive conditions of low oxygen, mainly under the control of a transcription complex known as hypoxia-inducible factor (HIF). Cancer cells also use HIF to adapt to the tumour environment; high HIFα levels are common in solid tumours, and for reasons that are not clear, correlate with a poor prognosis. A possible reason has been found in a study of the model organism Caenorhabditis elegans, which shows that HIFα inhibits the p53-mediated apoptosis (or cellular 'suicide') that normally prevents germ cells in which the DNA is damaged from becoming cancerous. Surprisingly, HIF acts in only two neurons and activates a tyrosinase that inhibits cell death in many other cells of C. elegans. This pathway also operates in tumour cells, as knockdown of the TYR-2 homologue TRP2 in melanoma cells increases apoptosis. But while protecting germ cells from self-destruction may be a lifesaver in worms rummaging in the soil, the pathway becomes a potential killer when turned on in a tumour. When oxygen levels drop in a tissue, the transcription factor hypoxia-inducible factor (HIF) is activated to regulate the cellular response. HIFα levels are increased in most solid tumours and this correlates with a poor prognosis, for unknown reasons. Here it is shown that HIF-1, the worm version of HIFα, protects germ cells from DNA-damage-induced death. It does this remotely, by increasing the production of the TYR-2 protein in distant neurons. Inhibiting a human TYR-2 homologue promotes apoptosis in melanoma cells.