YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells.
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Animals
Carcinoma, Renal Cell
/ genetics
Cell Line, Tumor
Glycolysis
Heterografts
Humans
Kidney Neoplasms
/ genetics
MAP Kinase Signaling System
Mice
Mice, SCID
Neurofibromatosis 2
/ genetics
Neurofibromin 2
/ deficiency
Oxidative Phosphorylation
Phosphatidylinositol 3-Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
Trans-Activators
Transcription Factors
/ antagonists & inhibitors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
YAP-Signaling Proteins
Hippo pathway
NF2
RAF-MEK-ERK pathway
ROS
TAZ
YAP
Journal
Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028
Informations de publication
Date de publication:
06 05 2019
06 05 2019
Historique:
received:
10
03
2018
revised:
04
02
2019
accepted:
08
04
2019
entrez:
8
5
2019
pubmed:
8
5
2019
medline:
7
1
2020
Statut:
ppublish
Résumé
Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome neurofibromatosis type 2 (NF2), as well as various sporadic cancers including kidney cancer. Multiple Merlin/NF2 effector pathways including the Hippo-YAP/TAZ pathway have been identified. However, the molecular mechanisms underpinning the growth and survival of NF2-mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors. Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and reactive oxygen species (ROS) buildup, resulting in oxidative-stress-induced cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPAC-dependent activation of RAF-MEK-ERK signaling as a resistance mechanism to YAP/TAZ inhibition. Finally, unbiased analysis of TCGA primary kidney tumor transcriptomes confirms a positive correlation of a YAP/TAZ signature with glycolysis and inverse correlations with oxidative phosphorylation and lysosomal gene expression, supporting the clinical relevance of our findings.
Identifiants
pubmed: 31063758
pii: S1534-5807(19)30284-9
doi: 10.1016/j.devcel.2019.04.014
pmc: PMC6524954
mid: NIHMS1526767
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Neurofibromin 2
0
Trans-Activators
0
Transcription Factors
0
Transcriptional Coactivator with PDZ-Binding Motif Proteins
0
WWTR1 protein, human
0
YAP-Signaling Proteins
0
YAP1 protein, human
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
425-443.e9Subventions
Organisme : NCI NIH HHS
ID : P50 CA101942
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134923
Pays : United States
Organisme : NIDCR NIH HHS
ID : R21 DE028670
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009686
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA187090
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA051008
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA193698
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Références
EMBO J. 2016 Mar 1;35(5):462-78
pubmed: 26668268
Mol Cell. 2017 Nov 2;68(3):591-604.e5
pubmed: 29100056
Nat Cell Biol. 2015 Jan;17(1):95-103
pubmed: 25438054
Hum Mol Genet. 2003 Jun 1;12(11):1211-21
pubmed: 12761036
Carcinogenesis. 2008 Nov;29(11):2139-46
pubmed: 18725387
FEBS J. 2006 Sep;273(18):4264-76
pubmed: 16930133
Cancer Discov. 2016 Nov;6(11):1258-1266
pubmed: 27604489
Circ Res. 2015 Jan 2;116(1):35-45
pubmed: 25249570
Mol Cell Biol. 2002 Jun;22(11):3717-28
pubmed: 11997508
EMBO J. 2018 Nov 15;37(22):
pubmed: 30348863
Oncotarget. 2014 Dec 30;5(24):12509-27
pubmed: 25587023
Cell Rep. 2016 Mar 15;14(10):2476-89
pubmed: 26947078
Dev Biol. 2012 Sep 1;369(1):115-23
pubmed: 22732571
J Clin Invest. 2018 Mar 1;128(3):1010-1025
pubmed: 29400692
Science. 1993 Nov 12;262(5136):1069-72
pubmed: 7694367
Eur Urol. 2016 Sep;70(3):516-21
pubmed: 26149668
Cell. 2012 Aug 17;150(4):780-91
pubmed: 22863277
Sci Signal. 2011 Oct 25;4(196):ra70
pubmed: 22028467
Genes Dev. 2013 Jun 1;27(11):1223-32
pubmed: 23752589
Dev Cell. 2001 Jul;1(1):63-72
pubmed: 11703924
Cell Metab. 2016 Nov 8;24(5):716-727
pubmed: 27746050
Cell. 2013 Sep 12;154(6):1342-55
pubmed: 24012335
N Engl J Med. 2016 Jan 14;374(2):135-45
pubmed: 26536169
J Cell Sci. 2013 May 1;126(Pt 9):1905-12
pubmed: 23720375
Cell Death Dis. 2016 Apr 21;7:e2198
pubmed: 27100892
Nat Commun. 2016 Oct 07;7:13131
pubmed: 27713405
Oncogene. 2016 Feb 4;35(5):537-48
pubmed: 25893302
Cancer Cell. 2014 Jul 14;26(1):48-60
pubmed: 25026211
Cell Metab. 2019 Jan 8;29(1):124-140.e10
pubmed: 30293773
Nat Cell Biol. 2016 Aug;18(8):886-896
pubmed: 27428308
Genes Dev. 2012 Sep 15;26(18):2027-37
pubmed: 22925885
Nature. 1998 Nov 12;396(6707):180-3
pubmed: 9823899
Eur Urol. 2016 Aug;70(2):348-57
pubmed: 26895810
Cancer Cell. 2015 Dec 14;28(6):743-757
pubmed: 26678338
J Biol Chem. 1999 Jul 16;274(29):20281-6
pubmed: 10400647
Cancer Res. 2006 Oct 1;66(19):9483-91
pubmed: 17018604
Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15038-43
pubmed: 17015830
Nat Cell Biol. 2015 Jun;17(6):793-803
pubmed: 25961504
Nat Commun. 2017 Jan 19;8:14073
pubmed: 28102225
Nat Cell Biol. 2012 Dec;14(12):1322-9
pubmed: 23143395
Oncogene. 2009 Feb 12;28(6):854-65
pubmed: 19029950
Oncotarget. 2018 Jan 10;9(12):10723-10733
pubmed: 29535838
Nat Cell Biol. 2017 Apr;19(4):362-374
pubmed: 28346439
Nature. 2017 Jun 22;546(7659):498-503
pubmed: 28607485
Cancer Res. 2016 Jun 15;76(12):3507-19
pubmed: 27216189
Mol Cell. 2018 Oct 18;72(2):328-340.e8
pubmed: 30293781
Dev Cell. 2016 Nov 21;39(4):452-465
pubmed: 27818180
Oncogene. 2012 Dec 6;31(49):5117-22
pubmed: 22286761
Cancer Res. 2004 Feb 1;64(3):985-93
pubmed: 14871829
Cell Rep. 2017 May 9;19(6):1083-1090
pubmed: 28494858
J Clin Invest. 2016 Sep 1;126(9):3313-35
pubmed: 27548520
Eur J Cancer. 2013 Jul;49(11):2608-18
pubmed: 23566416
Cell Rep. 2018 Apr 3;23(1):313-326.e5
pubmed: 29617669
Gastroenterology. 2018 Apr;154(5):1465-1479.e13
pubmed: 29305935
Cell Metab. 2014 Apr 1;19(4):630-41
pubmed: 24703695
J Biol Chem. 2010 Nov 26;285(48):37159-69
pubmed: 20858893
Cell. 2007 Sep 21;130(6):1120-33
pubmed: 17889654
Am J Physiol. 1994 Aug;267(2 Pt 1):C313-39
pubmed: 8074170
Eur Urol. 2018 Jan;73(1):71-78
pubmed: 28592388
Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):21064-9
pubmed: 21078993
Am J Med Genet A. 2012 Jan;158A(1):24-41
pubmed: 22140088
J Biol Chem. 2017 Oct 13;292(41):17046-17056
pubmed: 28848049
J Neurosci. 2006 Mar 29;26(13):3390-5
pubmed: 16571745
Oncogene. 2002 Mar 28;21(14):2236-44
pubmed: 11948406
Nat Cell Biol. 2015 Apr;17(4):500-10
pubmed: 25751140
J Biol Chem. 1997 Jul 11;272(28):17269-75
pubmed: 9211863
Mol Cell Biol. 2002 Sep;22(17):6023-33
pubmed: 12167697
Cell. 2014 Jun 5;157(6):1324-38
pubmed: 24906150
Neoplasia. 2008 Nov;10(11):1204-12
pubmed: 18953429
Genes Dev. 2007 Nov 1;21(21):2747-61
pubmed: 17974916
J Exp Med. 2014 Oct 20;211(11):2249-63
pubmed: 25288394
J Biol Chem. 2003 Oct 10;278(41):39337-48
pubmed: 12869574
Cancer Res. 2007 Jan 15;67(2):520-7
pubmed: 17234759
Brain Pathol. 2009 Jan;19(1):27-38
pubmed: 18445079
EMBO J. 2013 May 29;32(11):1543-55
pubmed: 23644383
Nat Cell Biol. 2014 Apr;16(4):357-66
pubmed: 24658687
Genes Dev. 2008 Jul 15;22(14):1962-71
pubmed: 18579750
Trends Cell Biol. 2016 Apr;26(4):289-299
pubmed: 26750334
Cancer Cell. 2011 Apr 12;19(4):527-40
pubmed: 21481793
Methods Enzymol. 2015;561:171-96
pubmed: 26358905
Nat Cell Biol. 2015 Apr;17(4):490-9
pubmed: 25751139
Mol Cell Biol. 2003 Oct;23(20):7315-28
pubmed: 14517300
Dev Cell. 2010 Feb 16;18(2):288-99
pubmed: 20159598
J Reprod Fertil. 1990 Jan;88(1):231-9
pubmed: 2313640
J Cell Biol. 2004 Feb 16;164(4):527-34
pubmed: 14769862
Nat Genet. 2015 Jan;47(1):13-21
pubmed: 25401301
Nature. 2015 Aug 20;524(7565):361-5
pubmed: 26168401
Genes Dev. 2001 Jun 1;15(11):1406-18
pubmed: 11390360
Cytometry A. 2014 Aug;85(8):729-37
pubmed: 24953340
Physiol Rev. 1990 Apr;70(2):391-425
pubmed: 2157230
Cell. 2005 Aug 12;122(3):421-34
pubmed: 16096061
Cell. 2010 Feb 19;140(4):477-90
pubmed: 20178741
Cancer Res. 2017 Apr 1;77(7):1637-1648
pubmed: 28202507
PLoS One. 2016 May 02;11(5):e0154684
pubmed: 27136098
Nat Rev Mol Cell Biol. 2010 Jan;11(1):50-61
pubmed: 19997129
Nat Genet. 2015 Mar;47(3):250-6
pubmed: 25665005
Nat Cell Biol. 2009 Dec;11(12):1444-50
pubmed: 19935651
Oncotarget. 2015 May 20;6(14):11768-78
pubmed: 26059435
Mol Cell Biol. 2009 Mar;29(6):1472-86
pubmed: 19103750
Science. 2011 Jun 17;332(6036):1429-33
pubmed: 21617040
Cell. 2002 Aug 23;110(4):467-78
pubmed: 12202036
Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18200-5
pubmed: 15598747
Genes Dev. 2010 Aug 15;24(16):1718-30
pubmed: 20675406
Autophagy. 2016 Oct 2;12(10):1954-1955
pubmed: 27485905
Genetics. 2016 Aug;203(4):1777-88
pubmed: 27317679
J Cell Biol. 2003 Jul 21;162(2):281-91
pubmed: 12876277
Mol Biol Cell. 2007 Apr;18(4):1437-46
pubmed: 17301289
EMBO J. 2017 Nov 15;36(22):3325-3335
pubmed: 28963395
Nature. 1993 May 6;363(6424):85-8
pubmed: 8479541
EMBO J. 2015 May 12;34(10):1349-70
pubmed: 25796446
Nature. 2010 Jan 21;463(7279):360-3
pubmed: 20054297
Nat Commun. 2017 May 05;8:15280
pubmed: 28474680
Nat Commun. 2013;4:2799
pubmed: 24240988
Dev Cell. 2010 Jul 20;19(1):27-38
pubmed: 20643348
Mol Cell. 2016 Dec 1;64(5):993-1008
pubmed: 27912098
J Neurooncol. 2015 Apr;122(2):313-20
pubmed: 25567352
Mol Cell. 2004 Dec 3;16(5):819-30
pubmed: 15574336