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

Fang Zheng, Jianing Chen, Xiaoqian Zhang, Zifeng Wang, Jiewen Chen, Xiaorong Lin, Hongyan Huang, Wenkui Fu, Jing Liang, Wei Wu, Bo Li, Herui Yao, Hai Hu () and Erwei Song ()
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Fang Zheng: Sun Yat-Sen University
Jianing Chen: Sun Yat-Sen University
Xiaoqian Zhang: Sun Yat-Sen University
Zifeng Wang: Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine
Jiewen Chen: Sun Yat-Sen University
Xiaorong Lin: Sun Yat-Sen University
Hongyan Huang: the First Affiliated Hospital of Chongqing Medical University
Wenkui Fu: Sun Yat-Sen University
Jing Liang: Peking University Health Science Center
Wei Wu: Sun Yat-Sen University
Bo Li: Sun Yat-Sen University
Herui Yao: Sun Yat-Sen University
Hai Hu: Sun Yat-Sen University
Erwei Song: Sun Yat-Sen University

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21535-3

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