Tat-activating regulatory DNA-binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520

Authors

  • Yun-Yong Park,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Sang-Bae Kim,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Hee Dong Han,

    1. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
    2. Research Center for Medicinal Chemistry, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Deajeon, South Korea
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  • Bo Hwa Sohn,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Ji Hoon Kim,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
    2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University School of Medicine, Seoul, Korea
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  • Jiyong Liang,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Yiling Lu,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Cristian Rodriguez-Aguayo,

    1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Gabriel Lopez-Berestein,

    1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
    2. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
    3. Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Gordon B. Mills,

    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Anil K. Sood,

    1. Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
    2. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
    3. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
    4. Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX
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  • Ju-Seog Lee

    Corresponding author
    1. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX
    2. Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, School of Medicine, Kyung Hee University, Seoul, Korea
    • Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 950, Houston, TX 77030===

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    • fax: 713-563-4235


  • Potential conflict of interest: Dr. Mills consults for and received grants from Astra Zeneca. He consults for and owns stock in Catena Pharmaceuticals. He also consults for Critical Outcome Technologies, Daiichi, Targeted Molecular Diagnotics, Foundation Medicine, Han AlBio Korea, Komen Foundation, Novartis, Symphogen, and Tau Therapeutics. He owns stock in PTV Ventures and Spindle Top Ventures. He received grants from Celgene, CeMines, Exelixis/Sanofi, GlaxoSmithKline, Roche, and Wyether/Pfizer/Puma.

  • This research is supported, in part, by the 2011 and 2012 cycle of MD Anderson Sister Institute Network Fund (to J-S.L.), 5U54 CA112970-08 (to G.B.M.), 5P01CA099031-07 (to G.B.M.), P30 CA016672 (to G.B.M.), and CA016672 (MD Anderson Cancer Center Support Grant) from the National Institutes of Health.

Abstract

Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers, including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer-specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat-activating regulatory DNA-binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate-limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the microRNA 520 (miR-520) family is an intermediate regulator of TARDBP-mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR-520 family, which, in turn, inhibited expression of PFKP. We further showed that expression of TARDBP is significantly associated with the overall survival of patients with HCC. Conclusion: Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC. (HEPATOLOGY 2013;)

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