Journal
HEPATOLOGY
Volume 63, Issue 1, Pages 159-172Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.28223
Keywords
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Funding
- University of Texas MD Anderson Cancer Center's Sister Institute Network Fund
- MD Anderson Cancer Center's Support Grant from the National Institutes of Health [CA016672]
- Bio RD Program [2014R1A2A2A01003983]
- National Research Foundation of Korea [2011-0018055, NRF-2013R1A2A2A05005990, NRF-2014R1A1A2053529]
- [5U54 CA112970-08]
- [5P01CA099031-07]
- [P30 CA016672]
- NATIONAL CANCER INSTITUTE [P30CA016672, U54CA112970, P01CA099031, R01CA150229] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK102611] Funding Source: NIH RePORTER
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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. (Hepatology 2016;63:159-172)
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