title: Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma.
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. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (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 solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (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 hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks 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 hepatocellular carcinoma.
  
  
  CONCLUSIONS
  YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets.
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.|ASAN Institute for Life Sciences, ASAN Medical Center, Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Yun-Yong
authors.initials: YY
authors.lastname: Park
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Bo Hwa
authors.initials: BH
authors.lastname: Sohn
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: ASAN Institute for Life Sciences, ASAN Medical Center, Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Myoung-Hee
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, South Korea.
authors.forename: Jae-Jun
authors.initials: JJ
authors.lastname: Shim
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pathology and Brain Korea 21 Project for Medical Science, Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Yoo
authors.affiliation: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jun Eul
authors.initials: JE
authors.lastname: Hwang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Life Sciences and Research Center for Cellular Homeostasis, Ewha Woman's University, Seoul, South Korea.
authors.forename: Woojin
authors.initials: W
authors.lastname: Jeong
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Inn Sun
authors.initials: IS
authors.lastname: Park
authors.affiliation: Department of Pathology and Brain Korea 21 Project for Medical Science, Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, South Korea.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.|Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.|Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D026905:Amino Acid Transport Systems / Q000502:physiology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D026905:Amino Acid Transport Systems; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases