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-1α-induced lincRNA-p21 is able to bind HIF-1α and VHL and thus 
disrupts the VHL-HIF-1α interaction. This disassociation attenuates VHL-mediated 
HIF-1α ubiquitination and causes HIF-1α accumulation. These data indicate the 
existence of a positive feedback loop between HIF-1α 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.