HILPS, a long noncoding RNA essential for global oxygen sensing in humans

Adaptation to low levels of oxygen (hypoxia) is a universal biological feature across metazoans. However, the unique mechanisms how different species sense oxygen deprivation remain unresolved. Here, we functionally characterize a novel long noncoding RNA (lncRNA), LOC105369301, which we termed hypoxia-induced lncRNA for polo-like kinase 1 (PLK1) stabilization (HILPS). HILPS exhibits appreciable basal expression exclusively in a wide variety of human normal and cancer cells and is robustly induced by hypoxia-inducible factor 1 alpha (HIF1 alpha). HILPS binds to PLK1 and sequesters it from proteasomal degradation. Stabilized PLK1 directly phosphorylates HIF1 alpha and enhances its stability, constituting a positive feed-forward circuit that reinforces oxygen sensing by HIF1 alpha. HILPS depletion triggers catastrophic adaptation defect during hypoxia in both normal and cancer cells. These findings introduce a mechanism that underlies the HIF1 alpha identity deeply interconnected with PLK1 integrity and identify the HILPS-PLK1-HIF1 alpha pathway as a unique oxygen-sensing axis in the regulation of human physiological and pathogenic processes.