Abstract
Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-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-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. 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-1α significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
Highlights
Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells
To investigate the contributions of HIF-1α in regulating glycolysis of cancer cells under hypoxia, we evaluated the dynamics of HIF-1α protein and its target genes related to glucose metabolism, including GLUT1, hexokinase II (HKII), lactate dehydrogenase A (LDHA), and PDK15, following prolonged hypoxia
HIF-1α protein peaked at 4 h after the MDAMB-231and MCF-7 breast cancer cells were placed under hypoxic conditions, and gradually reduced to background level at 48 h (Fig. 1a, Supplementary Fig. 1a), which was in agreement with findings from other groups[24,25,26]
Summary
Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. We demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing HIF-1α-mediated transactivation and glycolysis. Inhibiters of HIF-2 that disrupting HIF/ARNT dimer formation have been developed for cancer treatment[13,14] In this context, it is tempting to suggest that inhibiting HIF-1 mediated transactivation, rather than directly targeting the transcriptional factor itself, could be more promising for cancer treatment strategy, but such approaches are still lacking. There is a pressing need to elucidate the regulatory mechanisms of HIF-1 transactivation to develop effective strategies against hypoxia-mediated tumor progression. The PKM2/PHD3 complex is transported into the nucleus and assists recruitment of HIF-1 as well as p300 to form a transcriptional complex at the hypoxia response elements (HRE)[6]. Long noncoding RNAs (lncRNAs) are a class of non-proteincoding RNA transcripts that are longer than 200nt and are involved in numerous physiological and pathological processes through epigenetic regulation and related signal transduction[17,18,19,20]
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