Transcriptional regulation of cell polarity in EMT and cancer

Abstract

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.

Sorafenib inhibits transforming growth factor β1-Mediated Epithelial-Mesenchymal Transition and apoptosis in mouse hepatocytes

“…Indeed, in addition to Snail, an increasing number of genes have been shown to orchestrate EMT. 32 We further showed that sorafenib negatively regulated the expression of other EMT-related transcription factors, including Twist, Zeb1, and Zeb2, but only had a subtle effect on the mRNA level of Slug (Fig. 5D).…”

Separation and Characterization of Epithelial and Mesenchymal-like Murine Mammary Tumor Cells Reveals Epithelial Cell Differentiation Plasticity and Enhanced Tumorigenicity of Epithelial-enriched Tumor Cells

“…During EMT, adherent epithelial cells lose basal-apical polarity and acquire a mesenchymal phenotype that includes enhanced migratory capacity, invasiveness, resistance to apoptosis and an increased production of extracellular matrix components [1]. Some of the hallmarks of EMT include loss of CD24 cell surface expression [2][3][4], downregulation of epithelial cytokeratins 8, 18 and 19 and E-cadherin, upregulation of vimentin, and mesenchymal transcriptional regulators such as Snai1 (Snail), Snai2 (Slug), Zeb1, Zeb2, Twist, FOXC1, and FOXC2 as reviewed in [5]. Mesenchymal cancer cells are more resistant to conventional chemotherapy and radiotherapy and correlate with tumor recurrence and a poor prognosis [6], [7].…”

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

“…Snail is a conserved transcription factor that has been shown to play an important role in embryonic development and tumour progression 36 . Extensive analysis of such EMT inducers has clearly demonstrated a role in the direct regulation of cell polarity genes at the transcription level, contributing to the progression of cancer 37 . However, little information exists regarding the feedback regulation of these EMT inducers by cell polarity signalling.…”