One of the most prevalent and fundamentally important features of solid tumors, hypoxia contributes to the reprogramming of cancer metabolism from oxidative to glycolytic metabolism in cancer cells, thus maintaining redox homeostasis and cell survival under conditions of prolonged hypoxia. Previous studies have advanced our understanding of the mechanisms underlying hypoxia-induced cellular responses in cancer cells. In particular, transcription of several glycolytic genes vital to the Warburg effect (including hexokinase-2 (Hk2) and pyruvate kinase-M2 (Pkm2)), has been shown to be activated by hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcription factor. However, whether and how miRNAs are involved in regulating the glycolytic switch under hypoxia in cancer cells remains largely unexplored.
ZHANG Lingfei and his colleagues, under the supervision of Dr. LIU Mofang at the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, CAS, found 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. They demonstrate that this hypoxia-suppressed miR-199a plays a decisive role in limiting glycolysis in HCC cells by targeting Hk2 and Pkm2. Furthermore, systemically delivered cholesterol-modified agomiR-199a inhibits [18F]flurodeoxyglucose uptake and attenuates tumor growth in HCC tumor-bearing mice. These findings 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.
This work entitled “Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma” was published in The EMBO Journal on Sept 7, 2015. This work was collaborated with Drs. LOU Jiatao, GAO Chunfang, LI Biao, LI Yong, and LI Dangsheng.
This study was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.
AUTHOR CONTACT:
LIU Mofang，Principal Investigator
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Shanghai, China
Phone: 86-21-54921146;
E-mail: mfliu@sibcb.ac.cn
Fig. A model of miR-199a as a key regulatory node linking hypoxia to deregulated glucose metabolism in HCC (Image provided by Dr. LIU Mofang)
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