The Transcription Factor Snail Induces Tumor Cell Invasion through Modulation of the Epithelial Cell Differentiation Program

Craene, Bram De; Gilbert, Barbara; Stove, Christophe; Bruyneel, Erik; Roy, Frans Van; Berx, Geert

doi:10.1158/0008-5472.can-04-3545

Cited by 227 publications

(193 citation statements)

References 22 publications

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“…In fact, direct binding of SNAI1/SNAI2 to conserved E-box elements in the corresponding promoters has been reported for occludin, claudin-1 and claudin-7 (Ikenouchi et al, 2003;Martı´nez-Estrada et al, 2006). Interestingly, downregulation of claudin-4, the junctional adhesion molecule-1 (JAM-1/JAM-A) and Dlg3 has been detected in gene profiling studies of carcinoma cells, as well as in Madin-Darby canine kidney (MDCK) cells undergoing EMT after expression of SNAI1, SNAI2, E47 or other EMT regulators (De Craene et al, 2005b;Moreno-Bueno et al, 2006;Peinado et al, 2008). Because of the close relationship between tight junctions and the organization of epithelial cell polarity, these observations suggest that components of the core cell polarity complexes could also be direct targets of EMT transcriptional regulators.…”

Section: Regulation Of Cell Polarity Genes During Emtmentioning

confidence: 91%

“…Apart from E-cadherin, other epithelial genes initially downregulated by Snail and ZEB factors are components of the tight junctions, including occludin and several members of the claudin family (Ikenouchi et al, 2003;Ohkubo and Ozawa, 2004;De Craene et al, 2005b;Vandewalle et al, 2005;Martı´nez-Estrada et al, 2006). In fact, direct binding of SNAI1/SNAI2 to conserved E-box elements in the corresponding promoters has been reported for occludin, claudin-1 and claudin-7 (Ikenouchi et al, 2003;Martı´nez-Estrada et al, 2006).…”

Section: Regulation Of Cell Polarity Genes During Emtmentioning

confidence: 99%

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Transcriptional regulation of cell polarity in EMT and cancer

2008

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The epithelial-to-mesenchymal transition (EMT) is a crucial process in tumour progression providing tumour cells with the ability to escape from the primary tumour, to migrate to distant regions and to invade tissues. EMT requires a loss of cell-cell adhesion and apical-basal polarity, as well as the acquisition of a fibroblastoid motile phenotype. Several transcription factors have emerged in recent years that induce EMT, with important implications for tumour progression. However, their effects on cell polarity remain unclear. Here, we have re-examined the data available related to the effect of EMT related transcription factors on epithelial cell plasticity, focusing on their impact on cell polarity. Transcriptional and post-transcriptional regulatory mechanisms mediated by several inducers of EMT, in particular the ZEB and Snail factors, downregulate the expression and/or functional organization of core polarity complexes. We also summarize data on the expression of cell polarity genes in human tumours and analyse genetic interactions that highlight the existence of complex regulatory networks converging on the regulation of cell polarity by EMT inducers in human breast carcinomas. These recent observations provide new insights into the relationship between alterations in cell polarity components and EMT in cancer, opening new avenues for their potential use as therapeutic targets to prevent tumour progression.

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Section: Regulation Of Cell Polarity Genes During Emtmentioning

confidence: 91%

Section: Regulation Of Cell Polarity Genes During Emtmentioning

confidence: 99%

Transcriptional regulation of cell polarity in EMT and cancer

2008

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“…Cdx2, a transcription factor inducing intestinal metaplasia in the gastric epithelium, 31 has positively regulated the expression of claudin-4 during gastric carcinoma intestinal differentiation. 39,48 Snail and twist that have a central role in the epitheliummesenchymal transition (EMT), have been shown to repress claudin-4 expression in mouse epithelial cells, 49 colorectal cancer cells 50 and breast cancer cells. 51 In addition, tumorigenesis-associated TGF-b and Ras signaling pathways were reported to affect CLDN4 expression in pancreatic cancer cells.…”

Section: Bivalent Histone Modifications Are Associated With Cldn4 Repmentioning

confidence: 99%

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

Kwon

Kim

Jeong

et al. 2011

Laboratory Investigation

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The tight junction (TJ) protein claudin-4 is aberrantly upregulated in gastric cancer, but its clinical significance and the molecular mechanisms underlying claudin-4 overexpression in gastric cancer remain unclear. Here, we investigated its roles and epigenetic mechanisms regulating CLDN4 expression in gastric cancer. We show that increased membranous expression of claudin-4 in gastric carcinoma is associated with better patient prognosis, whereas cytoplasmic claudin-4 expression did not show a significant association with prognosis. Consistent with the correlation of increased membranous claudin-4 with favorable clinicopathological factors, claudin-4 overexpression inhibited the migration and invasion of gastric cancer cells; in contrast, it did not affect cell growth. Claudin-4 expression also increased the barrier function of TJs. Claudin-4 upregulation was strongly correlated with DNA hypomethylation in both gastric tissues and gastric cancer cells. Moreover, CLDN4 expression was repressed in normal gastric tissues in association with bivalent histone modifications, and loss of repressive histone methylations and gain of active histone modifications were associated with CLDN4 overexpression in gastric cancer cells. Interestingly, CLDN4 repression could be markedly derepressed by combined treatments that simultaneously target both histone modifications and DNA demethylation in CLDN4-hypermethylated cells, whereas concomitant changes in histone methylations and acetylations are required for CLDN4 induction in CLDN4-repressed cells with low DNA methylation. Taken together, this study reveals that membranous claudin-4 expression is associated with gastric cancer progression and that it is an independent positive prognosis marker in gastric carcinoma. Furthermore, our findings suggest that epigenetic derepression may be a possible mechanism underlying CLDN4 overexpression in gastric cancer and that claudin-4 may have potential as a promising target for the treatment of gastric cancer.

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“…This process is essential for gastrulation, neural crest formation, kidney development and so on (reviewed by Thiery, 2003). Several proteins have been identified that downregulate E-cadherin expression including SNAI1/SNAIL (Batlle et al, 2000;Cano et al, 2000), ZFHX1B/SIP1 (Comijn et al, 2001), SNAI2/SLUG (Hajra et al, 2002;De Craene et al, 2005), TWIST1 (Yang et al, 2004) and DeltaEF1 (Eger et al, 2005). Altered expression of these transcription factors seems to be also associated with an altered overexpression of transcriptional repressors of E-cadherin in tumour cells (Batlle et al, 2000;Cano et al, 2000;Comijn et al, 2001;Hajra et al, 2002;Yang et al, 2004;Eger et al, 2005).…”

mentioning

confidence: 99%

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

et al. 2006

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Using genome-wide expression profiling of a panel of 27 human mammary cell lines with different mechanisms of E-cadherin inactivation, we evaluated the relationship between E-cadherin status and gene expression levels. Expression profiles of cell lines with E-cadherin (CDH1) promoter methylation were significantly different from those with CDH1 expression or, surprisingly, those with CDH1 truncating mutations. Furthermore, we found no significant differentially expressed genes between cell lines with wild-type and mutated CDH1. The expression profile complied with the fibroblastic morphology of the cell lines with promoter methylation, suggestive of epithelial -mesenchymal transition (EMT). All other lines, also the cases with CDH1 mutations, had epithelial features. Three non-tumorigenic mammary cell lines derived from normal breast epithelium also showed CDH1 promoter methylation, a fibroblastic phenotype and expression profile. We suggest that CDH1 promoter methylation, but not mutational inactivation, is part of an entire programme, resulting in EMT and increased invasiveness in breast cancer. The molecular events that are part of this programme can be inferred from the differentially expressed genes and include genes from the TGFb pathway, transcription factors involved in CDH1 regulation (i.e. ZFHX1B, SNAI2, but not SNAI1, TWIST), annexins, AP1/2 transcription factors and members of the actin and intermediate filament cytoskeleton organisation.

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The Transcription Factor Snail Induces Tumor Cell Invasion through Modulation of the Epithelial Cell Differentiation Program

Abstract: Abberant activation of the process of epithelial-mesenchymal transition in cancer cells is a late event in tumor progression.

Cited by 227 publications

References 22 publications

Transcriptional regulation of cell polarity in EMT and cancer

Transcriptional regulation of cell polarity in EMT and cancer

Claudin-4 overexpression is associated with epigenetic derepression in gastric carcinoma

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

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