ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1

Abstract

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 corepressor. 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 b-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.

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…3,5,6,8 In carcinomas, ZEB1 coexpresses with b-catenin in undifferentiated tumor cells at their leading front, promoting invasiveness and metastasis. [27][28][29][30][31] We therefore decided to examine ZEB1 expression in a tissue microarray (TMA) of MCLs. ZEB1 was expressed in 50.0% of the cases for about 43.4% that were positive for b-catenin (Figure 1), (Supplementary Figures S1A and S1B).…”

“…20,26 In solid tumors, b-catenin colocalizes with the transcription factor ZEB1 in the nuclei of undifferentiated cancer cells at the invasive front. [27][28][29][30][31] Depending on the target gene, ZEB1 could function as either a transcriptional repressor or an activator through the recruitment of different cofactors. 29,[32][33][34][35] In malignant epithelial cells, ZEB1 triggers an epithelial-tomesenchymal transition (EMT), a process by which cancer cells acquire a pro-invasive phenotype.…”

“…[27][28][29][30][31] Depending on the target gene, ZEB1 could function as either a transcriptional repressor or an activator through the recruitment of different cofactors. 29,[32][33][34][35] In malignant epithelial cells, ZEB1 triggers an epithelial-tomesenchymal transition (EMT), a process by which cancer cells acquire a pro-invasive phenotype. 36,37 Consequently, in solid cancers, ZEB1 promotes tumor invasiveness and metastasis and correlates with poorer clinical prognosis.…”

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: A Review

“…The loss of E-cadherin is considered a crucial step in the progression of papilloma to invasive carcinoma (Perl et , 1998). It is regulated by a number of transcription factors such as Snail (Batlle et al, 2000), Twist (Yang et al, 2004) and ZEB1 (Sánchez-Tilló et al, 2010). The transcription factor Snail controls EMT by repressing E-cadherin expression (Cano et al, 2000).…”

Epithelial–mesenchymal transition in malignant mesothelioma

“…[8][9][10][11][12] These molecular markers repress the gene expression of E-cadherin, a marker of the epithelial phenotype. [7][8][9][13][14][15][16] MicroRNAs (or miRNAs) are a class of short noncoding RNAs that regulate gene expression in several physiological and pathological cellular processes. 17,18 Recently, miR-205 has been identified as a key regulator of epithelial-mesenchymal transition enforcing the epithelial phenotype.…”