HILPS, a novel long non-coding RNA essential for global oxygen sensing in human

Adaptation to low levels of O2 (hypoxia) is a universal biological feature across metazoans. Yet the underlying mechanisms how different species sense O2 deprivation remain to be deciphered. Here we functionally characterize a novel long non-coding RNA (lncRNA), LOC105369301, which we termed hypoxia-induced lncRNA for PLK1 stabilization or HILPS. HILPS exhibits appreciable basal expression exclusively in a broad range of human normal and cancer cells and is robustly induced by hypoxia inducible factor 1a (HIF1a). HILPS binds PLK1 and sequesters it from proteasome degradation. Stabilized PLK1 directly phosphorylates HIF1a and enhance its stability, constituting a positive feedforward circuit that reinforces oxygen sensing by HIF1a. HILPS inactivation triggers catastrophic adaptation defect during hypoxia in both normal and cancer cells. These findings introduce a mechanism that underlies the HIF1a identity deeply interconnected with PLK1 integrity, and identify the HILPS-PLK1-HIF1a pathway as a crucial oxygen-sensing axis in regulation of human physiological and pathogenic processes. Overall design: We performed RNA-Seq analysis in two normal cell lines (H9 and NCM460) and two cancer cell lines (RKO and MDA-MB-231) to screen and identify hypoxia/HIF1a/HIF1ß-induced lncRNAs. We further performed RNA-Seq analysis in H9 cells and human colorectal cancer organoids to investigate the function of HILPS under 1% O2.