Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma.
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.
Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Ling-Fei
LF
Zhang
Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Jia-Tao
JT
Lou
Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Ming-Hua
MH
Lu
Department of Laboratory Medicine, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China.
Chunfang
C
Gao
Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Shuang
S
Zhao
Department of Nuclear Medicine and Micro PET Center, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Biao
B
Li
Department of Nuclear Medicine, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Sheng
S
Liang
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Yong
Y
Li
Shanghai Information Center for Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Dangsheng
D
Li
Center for RNA Research, State Key Laboratory of Molecular Biology-University of Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences, Shanghai, China Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China mfliu@sibcb.ac.cn.
Mo-Fang
MF
Liu
D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000067780:ELAV-Like Protein 1 / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D011485:Protein Binding; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
D002352:Carrier Proteins; D000067780:ELAV-Like Protein 1; D006593:Hexokinase; D008565:Membrane Proteins; D035683:MicroRNAs; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C098770:ELAVL1 protein, human; C531408:mirn199 microRNA, human
HK2 and PKM2; glycolysis; hepatocellular carcinoma; hypoxia; miR‐199a