A Therapeutically Targetable TAZ-TEAD2 Pathway Drives the Growth of Hepatocellular Carcinoma via ANLN and KIF23.
Animals
Humans
Mice
Adaptor Proteins, Signal Transducing
/ genetics
Carcinoma, Hepatocellular
/ drug therapy
Cell Line, Tumor
Liver Neoplasms
/ drug therapy
Microtubule-Associated Proteins
/ metabolism
TEA Domain Transcription Factors
Transcription Factors
/ genetics
Tumor Microenvironment
YAP-Signaling Proteins
/ metabolism
Anillin
CRISPR
Combination Therapy
Immune Checkpoint Inhibition
Kinesin Family Member 23
Liver Cancer
Statin
Tyrosine Kinase Inhibitor
VT104
VT107
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
received:
17
06
2022
revised:
24
01
2023
accepted:
14
02
2023
pmc-release:
01
06
2024
medline:
23
5
2023
pubmed:
10
3
2023
entrez:
9
3
2023
Statut:
ppublish
Résumé
Despite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC. HCC was induced in mice by Sleeping Beauty-mediated expression of MET, CTNNB1-S45Y, or TAZ-S89A, or by diethylnitrosamine plus CCl YAP and TAZ were up-regulated in murine and human HCC, but only deletion of TAZ consistently decreased HCC growth and mortality. Conversely, overexpression of activated TAZ was sufficient to trigger HCC. TAZ expression in HCC was regulated by cholesterol synthesis, as demonstrated by pharmacologic or genetic inhibition of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1), or sterol regulatory element-binding protein 2 (SREBP2). TAZ- and MET/CTNNB1-S45Y-driven HCC required the expression of TEAD2 and, to a lesser extent, TEAD4. Accordingly, TEAD2 displayed the most profound effect on survival in patients with HCC. TAZ and TEAD2 promoted HCC via increased tumor cell proliferation, mediated by TAZ target genes ANLN and kinesin family member 23 (KIF23). Therapeutic targeting of HCC, using pan-TEAD inhibitors or the combination of a statin with sorafenib or anti-programmed cell death protein 1, decreased tumor growth. Our results suggest the cholesterol-TAZ-TEAD2-ANLN/KIF23 pathway as a mediator of HCC proliferation and tumor cell-intrinsic therapeutic target that could be synergistically combined with TIME-targeted therapies.
Sections du résumé
BACKGROUND & AIMS
Despite recent progress, long-term survival remains low for hepatocellular carcinoma (HCC). The most effective HCC therapies target the tumor immune microenvironment (TIME), and there are almost no therapies that directly target tumor cells. Here, we investigated the regulation and function of tumor cell-expressed Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HCC.
METHODS
HCC was induced in mice by Sleeping Beauty-mediated expression of MET, CTNNB1-S45Y, or TAZ-S89A, or by diethylnitrosamine plus CCl
RESULTS
YAP and TAZ were up-regulated in murine and human HCC, but only deletion of TAZ consistently decreased HCC growth and mortality. Conversely, overexpression of activated TAZ was sufficient to trigger HCC. TAZ expression in HCC was regulated by cholesterol synthesis, as demonstrated by pharmacologic or genetic inhibition of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMGCR), farnesyl pyrophosphate synthase, farnesyl-diphosphate farnesyltransferase 1 (FDFT1), or sterol regulatory element-binding protein 2 (SREBP2). TAZ- and MET/CTNNB1-S45Y-driven HCC required the expression of TEAD2 and, to a lesser extent, TEAD4. Accordingly, TEAD2 displayed the most profound effect on survival in patients with HCC. TAZ and TEAD2 promoted HCC via increased tumor cell proliferation, mediated by TAZ target genes ANLN and kinesin family member 23 (KIF23). Therapeutic targeting of HCC, using pan-TEAD inhibitors or the combination of a statin with sorafenib or anti-programmed cell death protein 1, decreased tumor growth.
CONCLUSIONS
Our results suggest the cholesterol-TAZ-TEAD2-ANLN/KIF23 pathway as a mediator of HCC proliferation and tumor cell-intrinsic therapeutic target that could be synergistically combined with TIME-targeted therapies.
Identifiants
pubmed: 36894036
pii: S0016-5085(23)00235-4
doi: 10.1053/j.gastro.2023.02.043
pmc: PMC10335360
mid: NIHMS1882252
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
anillin
0
KIF23 protein, human
0
Microtubule-Associated Proteins
0
TEA Domain Transcription Factors
0
TEAD2 protein, human
0
Tead2 protein, mouse
0
TEAD4 protein, human
0
Transcription Factors
0
YAP-Signaling Proteins
0
WWTR1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1279-1292Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK132710
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA259201
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190844
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116620
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA255621
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK123543
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228483
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233794
Pays : United States
Informations de copyright
Copyright © 2023. Published by Elsevier Inc.
Références
N Engl J Med. 2008 Jul 24;359(4):378-90
pubmed: 18650514
Nat Cell Biol. 2008 Jul;10(7):837-48
pubmed: 18568018
Cancer Discov. 2019 Aug;9(8):1124-1141
pubmed: 31186238
Gastroenterology. 2018 Apr;154(5):1421-1434
pubmed: 29274368
J Clin Invest. 2022 Jun 1;132(11):
pubmed: 35380992
Nat Rev Mol Cell Biol. 2019 Apr;20(4):211-226
pubmed: 30546055
Cell Rep. 2015 Mar 17;10(10):1692-1707
pubmed: 25772357
Cell. 2009 Nov 13;139(4):757-69
pubmed: 19914168
Nature. 2022 Oct;610(7931):356-365
pubmed: 36198802
J Immunol Res. 2014;2014:261365
pubmed: 24860833
Cell. 2019 Jan 24;176(3):564-580.e19
pubmed: 30580964
Cell Metab. 2020 May 5;31(5):969-986.e7
pubmed: 32259482
Lancet Oncol. 2022 Jan;23(1):77-90
pubmed: 34914889
Am J Pathol. 2019 May;189(5):1077-1090
pubmed: 30794805
J Biol Chem. 2009 May 15;284(20):13355-13362
pubmed: 19324877
Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18034-9
pubmed: 16332960
Lancet. 2017 Jun 24;389(10088):2492-2502
pubmed: 28434648
Ann Intern Med. 2019 Sep 3;171(5):318-327
pubmed: 31426090
Cancer Res. 2018 Mar 15;78(6):1457-1470
pubmed: 29339539
BMC Cancer. 2015 Dec 16;15:961
pubmed: 26674738
Nat Rev Drug Discov. 2020 Jul;19(7):480-494
pubmed: 32555376
Sci Rep. 2017 May 17;7(1):2035
pubmed: 28515457
Cancer. 2016 May 1;122(9):1312-37
pubmed: 26959385
Nat Protoc. 2013 Nov;8(11):2180-96
pubmed: 24136345
Cell Metab. 2016 Dec 13;24(6):848-862
pubmed: 28068223
J Clin Oncol. 2020 Jan 20;38(3):193-202
pubmed: 31790344
Gastroenterology. 2020 May;158(6):1698-1712.e14
pubmed: 31972235
Nat Rev Cancer. 2015 Feb;15(2):73-79
pubmed: 25592648
N Engl J Med. 2019 Apr 11;380(15):1450-1462
pubmed: 30970190
Int J Mol Sci. 2019 Feb 01;20(3):
pubmed: 30717258
Clin Cancer Res. 2019 May 15;25(10):3074-3083
pubmed: 30635339
Clin Cancer Res. 2019 Apr 1;25(7):2116-2126
pubmed: 30373752
Hepatology. 2020 May;71(5):1813-1830
pubmed: 31505040
Science. 2019 Nov 22;366(6468):1029-1034
pubmed: 31754005
Mol Cancer Ther. 2021 Jun;20(6):986-998
pubmed: 33850002
Trends Cancer. 2019 May;5(5):283-296
pubmed: 31174841
N Engl J Med. 2020 May 14;382(20):1894-1905
pubmed: 32402160
Curr Opin Cell Biol. 2019 Dec;61:64-71
pubmed: 31387016
Physiol Rev. 2014 Oct;94(4):1287-312
pubmed: 25287865
Nat Cell Biol. 2014 Apr;16(4):357-66
pubmed: 24658687
Hepatology. 2008 May;47(5):1714-24
pubmed: 18435462
J Clin Invest. 2002 May;109(9):1125-31
pubmed: 11994399
Gastroenterology. 2013 Feb;144(2):323-332
pubmed: 23063971
J Natl Cancer Inst. 2017 Sep 1;109(9):
pubmed: 28376154
Cell. 2017 Feb 9;168(4):584-599
pubmed: 28187282
Semin Liver Dis. 2019 May;39(2):261-274
pubmed: 30912094
J Hepatol. 2022 Jan;76(1):123-134
pubmed: 34464659
N Engl J Med. 2018 Jul 5;379(1):11-21
pubmed: 29972753
Nature. 2018 Aug;560(7718):291-292
pubmed: 30108348
J Cell Biochem. 2015 Nov;116(11):2465-75
pubmed: 25650113
Genes Dev. 2012 Jun 15;26(12):1300-5
pubmed: 22677547
Methods Mol Biol. 2015;1267:165-83
pubmed: 25636469
Dev Cell. 2010 Dec 14;19(6):831-44
pubmed: 21145499
Nat Cell Biol. 2018 Aug;20(8):888-899
pubmed: 30050119
Hepatology. 2018 Aug;68(2):663-676
pubmed: 29091290
Nat Rev Dis Primers. 2021 Jan 21;7(1):6
pubmed: 33479224
J Lipid Res. 2016 Mar;57(3):333-5
pubmed: 26798145
J Hepatol. 2022 Apr;76(4):910-920
pubmed: 34902531
Med Oncol. 2016 Nov;33(11):123
pubmed: 27734263