Premium
Suppression of miR‐199a maturation by HuR is crucial for hypoxia‐induced glycolytic switch in hepatocellular carcinoma
Author(s) -
Zhang LingFei,
Lou JiaTao,
Lu MingHua,
Gao Chunfang,
Zhao Shuang,
Li Biao,
Liang Sheng,
Li Yong,
Li Dangsheng,
Liu MoFang
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201591803
Subject(s) - biology , hepatocellular carcinoma , glycolysis , hypoxia (environmental) , cancer research , microrna , microbiology and biotechnology , genetics , metabolism , endocrinology , gene , oxygen , physics , quantum mechanics
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.