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 & 2 others Gordon Mills, Ju Seog Lee

Research output: Contribution to journalArticle

32 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 (US)
Pages (from-to)159-172
Number of pages14
JournalHepatology
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Amino Acid Transport Systems
Large Neutral Amino Acid-Transporter 1
Hepatocellular Carcinoma
Neoplasms
Proteins
Amino Acids
Metabolic Networks and Pathways
mechanistic target of rapamycin complex 1
Carcinogenesis
Cell Proliferation
Survival
Liver
Therapeutics
Growth

ASJC Scopus subject areas

  • Hepatology

Cite this

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. / 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; Lee, Ju Seog.

In: Hepatology, Vol. 63, No. 1, 01.01.2016, p. 159-172.

Research output: Contribution to journalArticle

Park, YY, Sohn, BH, Johnson, RL, Kang, MH, Kim, SB, Shim, JJ, Mangala, LS, Kim, JH, Yoo, JE, Rodriguez-Aguayo, C, Pradeep, S, Hwang, JE, Jang, HJ, Lee, HS, Rupaimoole, R, Lopez-Berestein, G, Jeong, W, Park, IS, Park, YN, Sood, AK, Mills, G & Lee, JS 2016, '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', Hepatology, vol. 63, no. 1, pp. 159-172. https://doi.org/10.1002/hep.28223
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 ; Lee, Ju Seog. / 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. In: Hepatology. 2016 ; Vol. 63, No. 1. pp. 159-172.
@article{62b10f1157674b3b8202ab7be2de9512,
title = "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",
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.",
author = "Park, {Yun Yong} and Sohn, {Bo Hwa} and Johnson, {Randy L.} and Kang, {Myoung Hee} and Kim, {Sang Bae} and Shim, {Jae Jun} and Mangala, {Lingegowda S.} and Kim, {Ji Hoon} and Yoo, {Jeong Eun} and Cristian Rodriguez-Aguayo and Sunila Pradeep and Hwang, {Jun Eul} and Jang, {Hee Jin} and Lee, {Hyun Sung} and Rajesha Rupaimoole and Gabriel Lopez-Berestein and Woojin Jeong and Park, {Inn Sun} and Park, {Young Nyun} and Sood, {Anil K.} and Gordon Mills and Lee, {Ju Seog}",
year = "2016",
month = "1",
day = "1",
doi = "10.1002/hep.28223",
language = "English (US)",
volume = "63",
pages = "159--172",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - 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

AU - Park, Yun Yong

AU - Sohn, Bo Hwa

AU - Johnson, Randy L.

AU - Kang, Myoung Hee

AU - Kim, Sang Bae

AU - Shim, Jae Jun

AU - Mangala, Lingegowda S.

AU - Kim, Ji Hoon

AU - Yoo, Jeong Eun

AU - Rodriguez-Aguayo, Cristian

AU - Pradeep, Sunila

AU - Hwang, Jun Eul

AU - Jang, Hee Jin

AU - Lee, Hyun Sung

AU - Rupaimoole, Rajesha

AU - Lopez-Berestein, Gabriel

AU - Jeong, Woojin

AU - Park, Inn Sun

AU - Park, Young Nyun

AU - Sood, Anil K.

AU - Mills, Gordon

AU - Lee, Ju Seog

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84952638769&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84952638769&partnerID=8YFLogxK

U2 - 10.1002/hep.28223

DO - 10.1002/hep.28223

M3 - Article

VL - 63

SP - 159

EP - 172

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 1

ER -