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. SoodGordon B. Mills, Ju Seog Lee

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)159-172
Number of pages14
JournalHepatology
Volume63
Issue number1
DOIs
Publication statusPublished - 2016 Jan 1

ASJC Scopus subject areas

  • Hepatology

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