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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
Author(s) -
Park YunYong,
Sohn Bo Hwa,
Johnson Randy L.,
Kang MyoungHee,
Kim Sang Bae,
Shim JaeJun,
Mangala Lingegowda S.,
Kim Ji Hoon,
Yoo Jeong Eun,
RodriguezAguayo Cristian,
Pradeep Sunila,
Hwang Jun Eul,
Jang HeeJin,
Lee HyunSung,
Rupaimoole Rajesha,
LopezBerestein Gabriel,
Jeong Woojin,
Park Inn Sun,
Park Young Nyun,
Sood Anil K.,
Mills Gordon B.,
Lee JuSeog
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28223
Subject(s) - yap1 , mtorc1 , biology , hippo signaling pathway , cancer research , carcinogenesis , amino acid transporter , microbiology and biotechnology , signal transduction , transcription factor , biochemistry , transporter , pi3k/akt/mtor pathway , gene
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. (H epatology 2016;63:159–172)