Journal Article

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

Zheng, Fang, Yao, Herui, Wu, Wei, Song, Erwei, Hu, Hai, Fu, Wenkui, Huang, Hongyan, Zhang, Xiaoqian, Li, Bo, Chen, Jianing, Lin, Xiaorong, Liang, Jing, Wang, Zifeng, Chen, Jiewen

2021

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/44 / 13/51 / 13/89 / 14/1 / 14/19 / 14/32 / 14/5 / 38/39 / 631/337/384/2568 / 631/67/2327 / 631/80 / Animals / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Carrier Proteins - metabolism / Feedback / Female / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Glycolysis - physiology / Humanities and Social Sciences / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism / Membrane Proteins - metabolism / Mice / Mice, Inbred BALB C / Mice, Nude / multidisciplinary / RNA, Long Noncoding - metabolism / Science / Science (multidisciplinary) / Thyroid Hormone-Binding Proteins / Thyroid Hormones - metabolism / Transcriptional Activation - physiology