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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

 Yun-Yong Park  ;  Bo Hwa Sohn  ;  Randy L. Johnson  ;  Myoung-Hee Kang  ;  Sang Bae Kim  ;  Jae-Jun Shim  ;  Lingegowda S. Mangala  ;  Ji Hoon Kim  ;  Jeong Eun Yoo  ;  Cristian Rodriguez-Aguayo  ;  Sunila Pradeep  ;  Jun Eul Hwang  ;  Hee-Jin Jang  ;  Hyun-Sung Lee  ;  Rajesha Rupaimoole  ;  Gabriel Lopez-Berestein  ;  Woojin Jeong  ;  Inn Sun Park  ;  Young Nyun Park  ;  Anil K. Sood  ;  Gordon B. Mills  ;  Ju-Seog Lee 
 HEPATOLOGY, Vol.63(1) : 159-172, 2016 
Journal Title
Issue Date
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoo, Jeong Eun(유정은)
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