Department of Urology, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China.
Sci Adv. 2023 Nov 24;9(47):eadi1867. doi: 10.1126/sciadv.adi1867. Epub 2023 Nov 22.
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), , which we termed hypoxia-induced lncRNA for polo-like kinase 1 (PLK1) stabilization (). exhibits appreciable basal expression exclusively in a wide variety of human normal and cancer cells and is robustly induced by hypoxia-inducible factor 1α (HIF1α). binds to PLK1 and sequesters it from proteasomal degradation. Stabilized PLK1 directly phosphorylates HIF1α and enhances its stability, constituting a positive feed-forward circuit that reinforces oxygen sensing by HIF1α. depletion triggers catastrophic adaptation defect during hypoxia in both normal and cancer cells. These findings introduce a mechanism that underlies the HIF1α identity deeply interconnected with PLK1 integrity and identify the -PLK1-HIF1α pathway as a unique oxygen-sensing axis in the regulation of human physiological and pathogenic processes.
适应低氧水平（缺氧）是后生动物中普遍存在的一种生物学特征。然而，不同物种感知缺氧的独特机制仍未得到解决。在这里，我们对一种新的长非编码 RNA（lncRNA）进行了功能表征，我们将其命名为缺氧诱导的 polo 样激酶 1（PLK1）稳定的 lncRNA（）。 仅在广泛的人类正常和癌细胞中具有可观的基础表达，并且被缺氧诱导因子 1α（HIF1α）强烈诱导。 与 PLK1 结合，并将其从蛋白酶体降解中隔离出来。稳定的 PLK1 直接磷酸化 HIF1α 并增强其稳定性，构成一个正反馈回路，增强 HIF1α 的氧感应。 在正常和癌细胞中， 耗竭会在缺氧期间引发灾难性的适应缺陷。这些发现引入了一种机制，该机制将 HIF1α 的特性与 PLK1 的完整性深深地联系在一起，并将 -PLK1-HIF1α 途径确定为调节人类生理和病理过程中独特的氧感应轴。
