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

By Kirsten Aigner, B. Dampier, L. Descovich, M. Mikula, Aneesa Sultan, M. Schreiber, W. Mikulits, Thomas Brabletz, D. Strand, P. Obrist and 6 more. Oncogene, 2007

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Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumourigenesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter assays. ZEB1 downregulation in undifferentiated cancer cells by RNA interference was sufficient to upregulate expression of these cell polarity genes on the RNA and protein level, to re-establish epithelial features and to impair cell motility in vitro. In human colorectal cancer, ZEB1 expression was limited to the tumour–host interface and was accompanied by loss of intercellular adhesion and tumour cell invasion. In invasive ductal and lobular breast cancer, upregulation of ZEB1 was stringently coupled to cancer cell dedifferentiation. Our data show that ZEB1 represents a key player in pathologic EMTs associated with tumour progression.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e057954b22e77ab5f4e65126e5751beff078eb9f

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Citations in the corpus

The ZEB/miR‐200 feedback loop—a motor of cellular plasticity in development and cancer? (2010, background): “Breast Increased levels in undifferentiated cancer cells of invasive ductal and lobular cancers Strongly increased levels in triple negative cancers Aigner et al, 2007 Graham et al, 2009 Ovarian Increased levels in metastasis Elloul et al, 2010 Endometrial Increased levels in highly aggressive type…”
Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “In addition to E-cadherin, ZEB proteins also directly downregulate the expression of tight junction genes and components of cell polarity complex to drive EMT (Aigner et al., 2007; Spaderna et al., 2008; Vandewalle et al., 2005).”
Transcriptional regulation of cell polarity in EMT and cancer (2008, background): “An inverse correlation has been established between ZEB1, an inducer of EMT, and LGL2 expression in invasive regions of colorectal and breast carcinomas (Aigner et al., 2007; Spaderna et al., 2008), supporting a causal function for the loss of polarity in tumour progression.”
A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells (2008, background): “Recently, we described that ZEB1 is a crucial EMT activator in human colorectal and breast cancer, and suppresses expression of basement membrane components (Spaderna et al, 2006) and cell polarity factors (Aigner et al, 2007; Spaderna et al, 2008).”
Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. (2008, background): “More recent studies have found that ZEB1, Snail, and Slug are capable of repressing the transcription of several polarity factors, including Crumbs3 and Lgl2 (Aigner et al., 2007; Spaderna et al., 2008), indicating their roles in suppressing critical components of epithelial cell traits.”
Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis (2015, result): “Experiments validating these predictions, again, fail to discriminate between the two models (45–47).”
Dynamic EMT: a multi‐tool for tumor progression (2021, neutral): “…of the disintegration of all epithelial junction complexes and of direct transcriptional repression of several members of the Crumbs and the Scribble complexes, apical – basal polarity is lost (Aigner et al , 2007; Moreno-Bueno et al , 2008; Spaderna et al , 2008; Lamouille et al , 2014) (Fig 1B).”