title: Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma.
abstract: YAP and its paralog protein TAZ are downstream effectors of the Hippo pathway. Both are amplified in many human cancers and promote cell proliferation and epithelial-mesenchymal transition. Little is known about the status of the Hippo pathway in cutaneous melanoma. We profiled Hippo pathway component expression in a panel of human melanoma cell lines and melanocytic lesions, and characterized the capacity of YAP and TAZ to control melanoma cell behavior. YAP and TAZ immuno-staining in human samples revealed mixed cytoplasmic and nuclear staining for both proteins in benign nevi and superficial spreading melanoma. TAZ was expressed at higher levels than YAP1/2 in all cell lines and in those with high invasive potential. Stable YAP or TAZ knockdown dramatically reduced the expression of the classical Hippo target CCN2/connective-tissue growth factor (CTGF), as well as anchorage-independent growth, capacity to invade Matrigel, and ability form lung metastases in mice following tail-vein injection. YAP knockdown also reduced invasion in a model of skin reconstruct. Inversely, YAP overexpression increased melanoma cell invasiveness, associated with increased TEA domain-dependent transcription and CCN2/CTGF expression. Together, these results demonstrate that both YAP and TAZ contribute to the invasive and metastatic capacity of melanoma cells and may represent worthy targets for therapeutic intervention.
authors.affiliation: Team "TGF-β and Oncogenesis", Centre de Recherche, Institut Curie, Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France.
authors.forename: Flore
authors.initials: F
authors.lastname: Nallet-Staub
authors.affiliation: Team "TGF-β and Oncogenesis", Centre de Recherche, Institut Curie, Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.affiliation: Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Team "TGF-β and Oncogenesis", Centre de Recherche, Institut Curie, Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France.
authors.forename: Cristèle
authors.initials: C
authors.lastname: Gilbert
authors.affiliation: Team "TGF-β and Oncogenesis", Centre de Recherche, Institut Curie, Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dodier
authors.affiliation: West Herts NHS Trust, Hertfordshire, London, UK.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bataille
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Sudol
authors.affiliation: Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Team "TGF-β and Oncogenesis", Centre de Recherche, Institut Curie, Orsay, France; INSERM U1021, Orsay, France; CNRS UMR 3347, Orsay, France. Electronic address: alain.mauviel@curie.fr.
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D000090683:Hippo Signaling Pathway; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D017346:Protein Serine-Threonine Kinases
references.citation: J Biol Chem. 2009 May 22;284(21):14347-58
references.pmid: 19324876
references.citation: J Biochem. 2011 Apr;149(4):361-79
references.pmid: 21324984
references.citation: Genes Dev. 2001 May 15;15(10):1229-41
references.pmid: 11358867
references.citation: Semin Cell Dev Biol. 2012 Sep;23(7):827-33
references.pmid: 22609812
references.citation: Cancer Res. 2008 Apr 15;68(8):2592-8
references.pmid: 18413727
references.citation: Oncogene. 2012 Apr 5;31(14):1743-56
references.pmid: 21874053
references.citation: Curr Biol. 2010 Jul 13;20(13):R574-82
references.pmid: 20619814
references.citation: Dev Dyn. 2012 Jan;241(1):3-15
references.pmid: 22174083
references.citation: Exp Oncol. 2010 Mar;32(1):2-9
references.pmid: 20332765
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):E2441-50
references.pmid: 22891335
references.citation: Dev Cell. 2010 Oct 19;19(4):491-505
references.pmid: 20951342
references.citation: J Vis Exp. 2011 Aug 03;(54):
references.pmid: 21847077
references.citation: Pigment Cell Melanoma Res. 2008 Apr;21(2):123-32
references.pmid: 18426405
references.citation: J Biol Chem. 2009 May 15;284(20):13355-13362
references.pmid: 19324877
references.citation: Growth Factors. 2008 Apr;26(2):80-91
references.pmid: 18428027
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1431-6
references.pmid: 20080598
references.citation: Nat Cell Biol. 2008 Jul;10(7):837-48
references.pmid: 18568018
references.citation: Pigment Cell Melanoma Res. 2008 Aug;21(4):429-38
references.pmid: 18541008
references.citation: Expert Opin Ther Targets. 2012 Mar;16(3):243-7
references.pmid: 22335485
references.citation: Mol Cell. 2003 Jan;11(1):11-23
references.pmid: 12535517
references.citation: Cancer Res. 2011 Jan 1;71(1):175-84
references.pmid: 21084275
references.citation: Genes Dev. 2010 May;24(9):862-74
references.pmid: 20439427
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10
references.pmid: 16894141
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1437-42
references.pmid: 20080689
references.citation: Curr Opin Cell Biol. 2008 Dec;20(6):638-46
references.pmid: 18955139
references.citation: Trends Cell Biol. 2012 Feb;22(2):88-96
references.pmid: 22153608
references.citation: Gene. 2012 Nov 10;509(2):215-22
references.pmid: 22939869
references.citation: Oncogene. 2002 Jul 25;21(32):4879-84
references.pmid: 12118366
references.citation: Cell. 2007 Sep 21;130(6):1120-33
references.pmid: 17889654
references.citation: Genes Dev. 2006 Aug 15;20(16):2149-82
references.pmid: 16912270
references.citation: Cancer Cell. 2009 Nov 6;16(5):425-38
references.pmid: 19878874
references.citation: Semin Ophthalmol. 2001 Dec;16(4):201-6
references.pmid: 15513441
references.citation: Cell. 2011 Mar 4;144(5):782-95
references.pmid: 21376238
references.citation: Genes Dev. 2008 Jul 15;22(14):1962-71
references.pmid: 18579750
references.citation: Biochem Soc Trans. 2012 Feb;40(1):124-8
references.pmid: 22260677
references.citation: Cancer Cell. 2008 Mar;13(3):188-92
references.pmid: 18328423
references.citation: FEBS Lett. 2001 Feb 16;490(3):190-5
references.pmid: 11223034
references.citation: J Cell Biol. 2005 Jul 4;170(1):49-59
references.pmid: 15983061
references.citation: Cancer Cell. 2003 Jun;3(6):537-49
references.pmid: 12842083
references.citation: Genes Dev. 2012 Jun 15;26(12):1300-5
references.pmid: 22677547
references.citation: Development. 2008 Dec;135(24):4059-69
references.pmid: 19004856
references.citation: J Natl Cancer Inst. 2010 Aug 4;102(15):1148-59
references.pmid: 20660365
references.citation: Oncogene. 2004 Sep 2;23(40):6726-35
references.pmid: 15273735
references.citation: J Cell Physiol. 2011 Apr;226(4):928-39
references.pmid: 20945341
references.citation: J Genet Genomics. 2011 Oct 20;38(10):471-81
references.pmid: 22035868
references.citation: Cancer Res. 1999 Feb 1;59(3):547-50
references.pmid: 9973198
references.citation: Cancer Res. 2007 Mar 1;67(5):2317-24
references.pmid: 17332363
references.citation: Genes Cancer. 2010 Nov;1(11):1115-8
references.pmid: 21779434
references.citation: Pigment Cell Melanoma Res. 2011 Oct;24(5):932-43
references.pmid: 21801332