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      YAP1 and TAZ Activates mTORC1 Pathway by Regulating Amino Acid Transporters in hepatocellular carcinoma

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          Abstract

          Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma (HCC). Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. YAP1 and TAZ are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/ TAZ regulates amino acid metabolism by up-regulating expression of the amino acid transporters SLC38A1 and SLC7A5. Subsequently, increased uptake of amino acids by the transporters activates mTORC1, a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in HCC patients. Furthermore, inhibition of the transporters and mTORC1 significantly block YAP1/TAZ-mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanism’s potential clinical implications for treating HCC.

          Conclusion

          YAP1 and TAZ regulate cancer metabolism and mTOCR1 through regulation of amino acid transportation and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets.

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          Author and article information

          Journal
          8302946
          4093
          Hepatology
          Hepatology
          Hepatology (Baltimore, Md.)
          0270-9139
          1527-3350
          9 October 2015
          26 November 2015
          January 2016
          01 January 2017
          : 63
          : 1
          : 159-172
          Affiliations
          [1 ]Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          [2 ]Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          [3 ]ASAN Institute for Life Sciences, ASAN Medical Center, Department of convergence Medicine, University of Ulsan College of Medicine, Seoul 138-736, Korea
          [4 ]Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          [5 ]Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, South Korea
          [6 ]Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          [7 ]Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          [8 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
          [9 ]Department of Pathology and Brain Korea 21 Project for Medical Science, Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, Korea
          [10 ]Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          [11 ]Department of Life Sciences and Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Korea
          [12 ]Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
          Author notes
          Corresponding author. Tel: +1 713 834 6154, fax: +1 713 563 4235, jlee@ 123456mdanderson.org
          Article
          PMC4881866 PMC4881866 4881866 nihpa724992
          10.1002/hep.28223
          4881866
          26389641
          Categories
          Article

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