Reciprocal Regulation of HIF-1 alpha and LincRNA-p21 Modulates the Warburg Effect

Hypoxia has long been linked to the Warburg effect, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the Warburg effect. Here we show that lincRNA-p21 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. Hypoxia/HIF-1 alpha-induced lincRNA-p21 is able to bind HIF-1 alpha and VHL and thus disrupts the VHL-HIF-1 alpha interaction. This disassociation attenuates VHL-mediated HIF-1 alpha ubiquitination and causes HIF-1 alpha accumulation. These data indicate the existence of a positive feedback loop between HIF-1 alpha and lincRNA-p21 that promotes glycolysis under hypoxia. The ability of lincRNA-p21 to promote tumor growth is validated in mouse xenograft models. Together, these findings suggest that lincRNA-p21 is an important player in the regulation of the Warburg effect and also implicate lincRNA-p21 as a valuable therapeutic target for cancer.