The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity

Aigner, Karl Reinhard; Dampier, Brigitta; Descovich, Luise; Mikula, Mario; Sultan, Aneesa; Schreiber, Martin; Mikulits, Wolfgang; Brabletz, Thomas; Strand, Dennis; Obrist, Peter; Sommergruber, Wolfgang; Schweifer, Norbert; Wernitznig, Andreas; Beug, Hartmut; Foisner, Roland; Eger, Andreas

doi:10.1038/sj.onc.1210508

Cited by 544 publications

(525 citation statements)

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“…Furthermore, expression profiling revealed a significant overlap between the gene sets affected by Fra-1 in EpH4 cells and data sets from human breast cancer cell lines, in which Zeb1 or Zeb2 expression had been targeted. 34,35 Consistent with the data from human cells, 14 RNA interference demonstrated that reducing the expression of Zeb1 and Zeb2, and to a lesser extent Zeb2 in EpFra1 cells, restored the expression of E-cadherin and most Zeb target genes and reduced migration and invasion in vitro. Interestingly, Zeb2 was decreased in Zeb1 knockdown cells and increased upon ectopic Zeb1 expression.…”

Section: Discussionsupporting

confidence: 73%

“…GSEA revealed that the promoters of the downregulated genes were enriched with TRE/CRE motifs, bound by AP-1, but also with E-boxes bound by Zeb/Slug proteins (Supplementary Table S1). Importantly, a significant overlap was found between the EpFra1 downregulated gene set and the genes upregulated in MDA-MB-231 cells following ZEB1 knockdown, 34 as well as genes modulated by ectopic ZEB2 expression in A431 cells 35 (Table 1b, Supplementary Figure S6d). Besides E-cadherin, decreased expression of several Zeb1/Zeb2 transcriptional targets, including polycistrons encoding for the miR-200 family, was confirmed by qRT-PCR (Figure 5c) and the expression of Zeb targets was largely restored upon Fra-1 knockdown (Supplementary Figure S6e).…”

Section: Resultsmentioning

confidence: 99%

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Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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“…showed that PI(3) kinase contributes to TrkB signaling as well (including anoikis resistance; Douma et al, 2004), in aggregate these data suggest a model in which TrkB activates multiple pathways, some of which critically depend on Zeb1 (Figure 7). Several reports have shown a correlation between Zeb1 expression and the aggressiveness of tumors, including those of endometrial (Spoelstra et al, 2006;Singh et al, 2008), colon (Pena et al, 2005;Aigner et al, 2007b), breast (Aigner et al, 2007a), lung (Dohadwala et al, 2006), gallbladder (Adachi et al, 2009), ovarian (Bendoraite et al, 2010) and prostate origin (Graham et al, 2008). In colon cancer, Zeb1 expression is linked to loss of the basement membrane, which correlates with increased metastasis (Spaderna et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Smit

Peeper

2011

Oncogene

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Anoikis (detachment-induced apoptosis) prevents the survival of cells at inappropriate sites of the body and can therefore act as a barrier to metastasis. In a functionbased genome-wide screen, we have previously identified the neurotrophic tyrosine kinase receptor TrkB as a potent suppressor of anoikis. Consistently, activated TrkB oncogenically transforms non-malignant epithelial cells and causes them to invade and produce metastatic tumors in vivo. Overexpression of activated TrkB also results in morphological transformation, resembling epithelial-mesenchymal transition (EMT). E-cadherin, an important EMT regulator, and two E-cadherin repressors, Twist and Snail, are critical for these TrkB functions. As Snail has been shown to induce Zeb1, another E-cadherin repressor, we hypothesized that Zeb1 could be a TrkB target, too. We show here that Zeb1 is required for TrkB-induced EMT in epithelial cells, as RNAi-mediated knockdown of Zeb1 reverted the morphological changes induced by TrkB. Furthermore, Zeb1 is involved in TrkB-induced anoikis resistance, migration and invasion. In vivo, knockdown of Zeb1 strongly reduced TrkB-induced metastasis. Finally, epistasis experiments showed that Zeb1 acts downstream of Twist and Snail. We conclude that Zeb1 is required for several TrkB-induced effects in vitro and in vivo, including metastasis.

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“…Actually, ZEB factors and miR200 reciprocally control their expression in a strict feedback loop [133]. Of note, ZEB1 is a key EMT regulator in many human cancers including prostate, colon, breast and pancreatic [132,[134][135][136], while miR200 family members are often down-regulated in cancer cells [131]. Actually, the regulation of EMT by miRNAs is a very general phenomenon not limited to TrkB signalling [137].…”

Section: Taddei Et Almentioning

confidence: 99%

Anoikis: an emerging hallmark in health and diseases

Taddei

Giannoni

Fiaschi

et al. 2011

The Journal of Pathology

466

404

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Anoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage-independent growth and epithelial-mesenchymal transition, two features associated with anoikis resistance, are crucial steps during tumour progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on their regulation in physiological processes, as well as in several diseases, including metastatic cancers, cardiovascular diseases and diabetes.

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The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity

Cited by 544 publications

References 39 publications

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis

Anoikis: an emerging hallmark in health and diseases

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