PMID- 26389641 OWN - NLM STAT- MEDLINE DCOM- 20160510 LR - 20211203 IS - 1527-3350 (Electronic) IS - 0270-9139 (Print) IS - 0270-9139 (Linking) VI - 63 IP - 1 DP - 2016 Jan TI - 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. PG - 159-72 LID - 10.1002/hep.28223 [doi] AB - 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. CONCLUSION: 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. CI - (c) 2015 by the American Association for the Study of Liver Diseases. FAU - Park, Yun-Yong AU - Park YY AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - ASAN Institute for Life Sciences, ASAN Medical Center, Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea. FAU - Sohn, Bo Hwa AU - Sohn BH AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Johnson, Randy L AU - Johnson RL AD - Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Kang, Myoung-Hee AU - Kang MH AD - ASAN Institute for Life Sciences, ASAN Medical Center, Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, South Korea. FAU - Kim, Sang Bae AU - Kim SB AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Shim, Jae-Jun AU - Shim JJ AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, South Korea. FAU - Mangala, Lingegowda S AU - Mangala LS AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Kim, Ji Hoon AU - Kim JH AD - Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea. FAU - Yoo, Jeong Eun AU - Yoo JE AD - Department of Pathology and Brain Korea 21 Project for Medical Science, Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, South Korea. FAU - Rodriguez-Aguayo, Cristian AU - Rodriguez-Aguayo C AD - Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Pradeep, Sunila AU - Pradeep S AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Hwang, Jun Eul AU - Hwang JE AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Jang, Hee-Jin AU - Jang HJ AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Lee, Hyun-Sung AU - Lee HS AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Rupaimoole, Rajesha AU - Rupaimoole R AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Lopez-Berestein, Gabriel AU - Lopez-Berestein G AD - Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Jeong, Woojin AU - Jeong W AD - Department of Life Sciences and Research Center for Cellular Homeostasis, Ewha Woman's University, Seoul, South Korea. FAU - Park, Inn Sun AU - Park IS AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Park, Young Nyun AU - Park YN AD - Department of Pathology and Brain Korea 21 Project for Medical Science, Institute for Medical Convergence, Yonsei University College of Medicine, Seoul, South Korea. FAU - Sood, Anil K AU - Sood AK AD - Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Mills, Gordon B AU - Mills GB AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Lee, Ju-Seog AU - Lee JS AD - Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX. AD - Kleberg Center for Molecular Markers, The University of Texas MD Anderson Cancer Center, Houston, TX. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - 5P01CA099031-07/CA/NCI NIH HHS/United States GR - CA016672/CA/NCI NIH HHS/United States GR - R01 DK102611/DK/NIDDK NIH HHS/United States GR - R01 CA150229/CA/NCI NIH HHS/United States GR - U54 CA112970/CA/NCI NIH HHS/United States GR - 5U54 CA112970-08/CA/NCI NIH HHS/United States GR - P01 CA099031/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151126 PL - United States TA - Hepatology JT - Hepatology (Baltimore, Md.) JID - 8302946 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Amino Acid Transport Systems) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Multiprotein Complexes) RN - 0 (Phosphoproteins) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 0 (Transcriptional Coactivator with PDZ-Binding Motif Proteins) RN - 0 (WWTR1 protein, human) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Adaptor Proteins, Signal Transducing/genetics/*physiology MH - Amino Acid Transport Systems/*physiology MH - Animals MH - Carcinoma, Hepatocellular/genetics/*metabolism MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Intracellular Signaling Peptides and Proteins/*physiology MH - Liver Neoplasms/genetics/*metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice MH - Multiprotein Complexes/*physiology MH - Phosphoproteins/genetics/*physiology MH - Protein Structure, Tertiary MH - Signal Transduction MH - TOR Serine-Threonine Kinases/*physiology MH - Trans-Activators MH - Transcription Factors MH - Transcriptional Coactivator with PDZ-Binding Motif Proteins MH - YAP-Signaling Proteins PMC - PMC4881866 MID - NIHMS724992 COIS- The authors have no conflicts of interest. EDAT- 2015/09/22 06:00 MHDA- 2016/05/11 06:00 PMCR- 2017/01/01 CRDT- 2015/09/22 06:00 PHST- 2015/06/03 00:00 [received] PHST- 2015/09/13 00:00 [accepted] PHST- 2015/09/22 06:00 [entrez] PHST- 2015/09/22 06:00 [pubmed] PHST- 2016/05/11 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - 10.1002/hep.28223 [doi] PST - ppublish SO - Hepatology. 2016 Jan;63(1):159-72. doi: 10.1002/hep.28223. Epub 2015 Nov 26.