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

• Published in: Hepatology (Baltimore, Md.) Vol. 63; no. 1; pp. 159 - 172
• Main Authors: Park, Yun‐Yong, Sohn, Bo Hwa, Johnson, Randy L., Kang, Myoung‐Hee, Kim, Sang Bae, Shim, Jae‐Jun, Mangala, Lingegowda S., Kim, Ji Hoon, Yoo, Jeong Eun, Rodriguez‐Aguayo, Cristian, Pradeep, Sunila, Hwang, Jun Eul, Jang, Hee‐Jin, Lee, Hyun‐Sung, Rupaimoole, Rajesha, Lopez‐Berestein, Gabriel, Jeong, Woojin, Park, Inn Sun, Park, Young Nyun, Sood, Anil K., Mills, Gordon B., Lee, Ju‐Seog
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer Health, Inc 01.01.2016
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - physiology; Amino Acid Transport Systems - physiology; Amino acids; Animals; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell growth; Cell proliferation; Female; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatology; Humans; Intracellular Signaling Peptides and Proteins - physiology; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Mechanistic Target of Rapamycin Complex 1; Metabolic activation; Metabolic pathways; Metabolic rate; Metabolism; Mice; Multiprotein Complexes - physiology; Phosphoproteins - genetics; Phosphoproteins - physiology; Protein Structure, Tertiary; Rapamycin; Signal Transduction; TOR protein; TOR Serine-Threonine Kinases - physiology; Trans-Activators; Transcription; Transcription Factors; Tumor suppressor genes; Tumorigenesis; Yes-associated protein
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.28223

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)