Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma.

Abstract

Glucose metabolic reprogramming is a hallmark of cancer. Cancer cells rapidly adjust their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch is still incompletely understood. Here, we report that hypoxia potently induces the RNA-binding protein HuR to specifically bind primary miR-199a transcript to block miR-199a maturation in hepatocellular carcinoma (HCC) cells. We demonstrate that this hypoxia-suppressed miR-199a plays a decisive role in limiting glycolysis in HCC cells by targeting hexokinase-2 (Hk2) and pyruvate kinase-M2 (Pkm2). Furthermore, systemically delivered cholesterol-modified agomiR-199a inhibits [(18)F]-fluorodeoxyglucose uptake and attenuates tumor growth in HCC tumor-bearing mice. These data reveal a novel mechanism of reprogramming of cancer energy metabolism in which HuR suppresses miR-199a maturation to link hypoxia to the Warburg effect and suggest a promising therapeutic strategy that targets miR-199a to interrupt cancerous aerobic glycolysis.

• Authors: Ling-Fei Zhang, Jia-Tao Lou, Ming-Hua Lu, Chunfang Gao, Shuang Zhao, Biao Li, Sheng Liang, Yong Li, Dangsheng Li, Mo-Fang Liu
• Journal: The EMBO journal (EMBO J) Vol. 34 Issue 21 Pg. 2671-85 (Nov 03 2015) ISSN: 1460-2075 [Electronic] England
• PMID: 26346275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors.

Chemical References

• Carrier Proteins
• ELAV-Like Protein 1
• ELAVL1 protein, human
• Membrane Proteins
• MicroRNAs
• Thyroid Hormones
• mirn199 microRNA, human
• thyroid hormone-binding proteins
• Hexokinase

Topics

• Animals
• Base Sequence
• Carcinoma, Hepatocellular (genetics, metabolism)
• Carrier Proteins (genetics, metabolism)
• Cell Hypoxia
• Cell Line, Tumor
• ELAV-Like Protein 1 (physiology)
• Gene Expression Regulation, Neoplastic
• Glycolysis
• Hexokinase (genetics, metabolism)
• Humans
• Liver Neoplasms (genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Transplantation
• Protein Binding
• Thyroid Hormones (genetics, metabolism)