ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1.
Loss of E-cadherin is a key initial step in the transdifferentiation of epithelial cells to a mesenchymal phenotype, which occurs when tumor epithelial cells invade into surrounding tissues. Expression of the nuclear factor ZEB1 induces an epithelial-to-mesenchymal transition and confers a metastatic phenotype on carcinomas by repressing the E-cadherin gene at the transcriptional level. In this study, we show that ZEB1 interacts with the SWI/SNF chromatin-remodeling protein BRG1 to regulate E-cadherin independently of CtBP, its traditional co-repressor. Blocking the interaction between ZEB1 and BRG1 induces expression of E-cadherin and downregulation of the mesenchymal marker vimentin. ZEB1 and BRG1 colocalize in E-cadherin-negative cells from cancer lines and in the stroma of normal colon. Colocalization of ZEB1 and BRG1 in epithelial cells is only found in those de-differentiated cells characterized by nuclear beta-catenin staining at the invasive edge of the tumor. Our results identify ZEB1/BRG1 as a new transcriptional mechanism regulating E-cadherin expression and epithelial-to-mesenchymal transdifferentiation that may be involved during the initial stages of tumor invasion.
Sánchez-Tilló
E
E
Group of Transcriptional Regulation, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
Lázaro
A
A
Torrent
R
R
Cuatrecasas
M
M
Vaquero
E C
EC
Castells
A
A
Engel
P
P
Postigo
A
A
D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D003106:Colon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C084108:SMARCA4 protein, human; D004265:DNA Helicases