ZEB2 upregulates integrin α5 expression through cooperation with Sp1 to induce invasion during epithelial–mesenchymal transition of human cancer cells
Open Access
- 6 January 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 33 (3), 563-571
- https://doi.org/10.1093/carcin/bgs005
Abstract
Epithelial–mesenchymal transition (EMT) is a process implicated in tumor invasion, metastasis, embryonic development and wound healing. ZEB2 is a transcription factor involved in EMT that represses E-cadherin transcription. Although E-cadherin downregulation is a major event during EMT and tumor progression, E-cadherin reduction is probably not sufficient for full invasiveness. The mechanisms by which E-cadherin transcriptional repressors induce mesenchymal genes during EMT remain largely unknown. Here, we investigated the role of ZEB2 in the induction of integrin α5 during cancer EMT and its underlying mechanism. In human cancer cells, ZEB2 was found to directly upregulate integrin α5 transcription in a manner that is independent of the regulation of E-cadherin expression. Conversely, depletion of ZEB2 by small interfering RNA suppressed integrin α5 expression, leading to reduced invasion. Suppression of integrin α5 inhibited cancer cell invasion, suggesting an important role for integrin α5 in cancer progression. Furthermore, ZEB2 was found to activate the integrin α5 and vimentin promoters by interacting with and activating the transcription factor Sp1, suggesting that cooperation between ZEB2 and Sp1 represents a novel mechanism of mesenchymal gene activation during EMT. These findings increase our understanding of the pathways beyond E-cadherin reduction that regulate mesenchymal gene expression during EMT and cancer progression.Keywords
This publication has 40 references indexed in Scilit:
- ZEB1 Coordinately Regulates Laminin-332 and β4 Integrin Expression Altering the Invasive Phenotype of Prostate Cancer Cells*Online Journal of Public Health Informatics, 2010
- Epithelial-Mesenchymal Transitions in Development and DiseaseCell, 2009
- The basics of epithelial-mesenchymal transitionJCI Insight, 2009
- Biomarkers for epithelial-mesenchymal transitionsJCI Insight, 2009
- Promoter-independent regulation of vimentin expression in mammary epithelial cells by val12ras and TGFβExperimental Cell Research, 2007
- The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarityOncogene, 2007
- Complex networks orchestrate epithelial–mesenchymal transitionsNature Reviews Molecular Cell Biology, 2006
- Interaction between integrin α5 and fibronectin is required for metastasis of B16F10 melanoma cellsBiochemical and Biophysical Research Communications, 2005
- Cell adhesion and signalling by cadherins and Ig-CAMs in cancerNature Reviews Cancer, 2004
- Epithelial integrinsBioEssays, 1996