title: Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial-mesenchymal transition-like phenotype in melanoma.
abstract: The E-box-binding zinc finger transcription factors Slug and ZEB1 are important repressors of E-cadherin, contributing to epithelial-mesenchymal transition (EMT) in primary epithelial cancers. Activator or repressor status of EMT transcription factors defines consequences for tumorigenesis. We show that changes in expression levels of Slug in melanoma cell lines lead to concomitant alterations of ZEB1 expression. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays identified Slug as a direct transcriptional activator at E-boxes of the ZEB1 promoter. Transcriptional activation of ZEB1 was demonstrated to be specific for Slug, as EMT regulators Snail and Twist failed to influence ZEB1 expression. Slug and ZEB1 cooperatively repressed E-cadherin expression resulting in decreased adhesion to human keratinocytes, but promoted migration of melanoma cells. Our results show that the transcriptional activity of ZEB1 is increased by Slug, suggesting a hierarchical organized expression of EMT transcription factors through directed activation, triggering an EMT-like process in melanoma.
authors: Cancer Biology Unit, Department of Dermatology, Medical University Graz, Graz, Austria.
authors: Christian
authors: C
authors: Wels
authors: Shripad
authors: S
authors: Joshi
authors: Petra
authors: P
authors: Koefinger
authors: Helmut
authors: H
authors: Bergler
authors: Helmut
authors: H
authors: Schaider
references: Oncogene. 2005 Mar 31;24(14):2375-85
references: 15674322
references: Am J Pathol. 2000 May;156(5):1515-25
references: 10793063
references: Biochem J. 2006 Mar 1;394(Pt 2):449-57
references: 16232121
references: J Cell Biol. 1991 Apr;113(1):173-85
references: 2007622
references: J Biol Chem. 2002 Oct 18;277(42):39209-16
references: 12161443
references: Gastroenterology. 2006 Sep;131(3):830-40
references: 16952552
references: J Biol Chem. 2001 Jul 20;276(29):27424-31
references: 11309385
references: World J Gastroenterol. 2008 Feb 21;14(7):1044-52
references: 18286686
references: Development. 2005 Jul;132(14):3151-61
references: 15983400
references: Cell Mol Life Sci. 2009 Mar;66(5):773-87
references: 19011757
references: Curr Opin Cell Biol. 2005 Oct;17(5):548-58
references: 16098727
references: Oncogene. 2007 Feb 22;26(8):1222-30
references: 16924233
references: Development. 2002 Apr;129(7):1583-93
references: 11923196
references: Cancer Res. 2008 Apr 1;68(7):2479-88
references: 18381457
references: Nat Genet. 2005 Oct;37(10):1047-54
references: 16142232
references: Cancer Res. 2006 Mar 1;66(5):2725-31
references: 16510593
references: Nat Cell Biol. 2000 Feb;2(2):84-9
references: 10655587
references: J Biol Chem. 2006 Jul 28;281(30):21321-21331
references: 16707493
references: J Biol Chem. 2001 Jul 6;276(27):24661-6
references: 11323412
references: Mol Cell. 2001 Jun;7(6):1267-78
references: 11430829
references: J Clin Invest. 2009 Jun;119(6):1420-8
references: 19487818
references: Cancer Res. 2006 Oct 1;66(19):9543-56
references: 17018611
references: Cancer Res. 2010 May 15;70(10):4174-84
references: 20424117
references: Mol Cell Endocrinol. 2002 Jun 28;192(1-2):85-91
references: 12088870
references: Cancer Res. 2007 Apr 1;67(7):3450-60
references: 17409456
references: Mol Cell Biol. 2004 Sep;24(17):7559-66
references: 15314165
references: Cancer Res. 2008 Oct 1;68(19):7846-54
references: 18829540
references: Curr Opin Cell Biol. 2003 Dec;15(6):740-6
references: 14644200
references: Mol Biol Cell. 2007 Sep;18(9):3533-44
references: 17615296
references: J Cell Biol. 1989 Jun;108(6):2435-47
references: 2661563
references: Neoplasia. 2009 Dec;11(12):1371-82
references: 20019845
references: J Biol Chem. 2005 Apr 29;280(17):17163-71
references: 15734731
references: Biochim Biophys Acta. 2010 Feb;1802(2):301-12
references: 20006705
references: Cell. 2009 Nov 25;139(5):871-90
references: 19945376
references: Cancer Res. 2004 Aug 1;64(15):5270-82
references: 15289333
references: Mol Biol Cell. 2008 Nov;19(11):4875-87
references: 18799618
references: Cancer Res. 2008 Jan 15;68(2):537-44
references: 18199550
references: Oncogene. 2007 Feb 1;26(5):711-24
references: 16862183
references: Cell. 2004 Jun 25;117(7):927-39
references: 15210113
references: Nat Cell Biol. 2008 May;10(5):593-601
references: 18376396
references: Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54
references: 20713713
references: Cancer Res. 2002 Mar 15;62(6):1613-8
references: 11912130
references: EMBO Rep. 2010 Sep;11(9):670-7
references: 20706219
references: Oncogene. 2007 Oct 25;26(49):6979-88
references: 17486063
references: BMC Cell Biol. 2009 Dec 21;10:94
references: 20025777
references: J Cell Sci. 2003 Feb 1;116(Pt 3):499-511
references: 12508111
references: Mol Biol Cell. 2009 Apr;20(8):2207-17
references: 19225155