The HIF-1α antisense long non-coding RNA drives a positive feedback loop of HIF-1α mediated transactivation and glycolysis

Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1 alpha anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1 alpha -mediated transactivation and glycolysis. Mechanistically, HIFAL recruits prolyl hydroxylase 3 (PHD3) to pyruvate kinase 2 (PKM2) to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance HIF-1 alpha transactivation. Reciprocally, HIF-1 alpha induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1 alpha. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1 alpha significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1 alpha -driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment. HIF1alpha is reported to drive tumourigenesis through activating glycolysis. Here, the authors show that HIFAL, the HIF1alpha antisense long non-coding RNA, and HIF1alpha form a positive feed-forward loop which is essential for HIF1a-mediated metabolic reprogramming and oncogenic role.