Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression

Significance Hypoxia-inducible factor 1α (HIF-1α) is required for adaptive changes to low oxygen levels, which include a reduced rate of cell division. However, many cell types continue to proliferate under hypoxic conditions. Here, we show that cyclin-dependent kinases 1 and 2 physically and functionally interact with HIF-1α, inhibiting and promoting its degradation by lysosomes, respectively. Cancer cells that proliferate under hypoxia failed to do so when treated with lysosome inhibitors. Our studies reveal that HIF-1α levels are coupled to phases of the cell cycle through lysosomal degradation and identify a novel role for the lysosome as a regulator of cell-cycle progression under hypoxic conditions.