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Regulatory networks defining EMT during cancer initiation and progression

Key Points

  • Epithelial to mesenchymal transition (EMT) will lead to reversible reprogramming of the cell, which is defined by fundamental changes initiated and maintained by several regulatory circuits.

  • EMT is well known to be transcriptionally regulated. Several transcription factors have been described as potent enough to drive EMT. The often strong interconnection between these factors forms a solid network that drives tumour progression.

  • Recent evidence has linked EMT to epigenetic modifications. These are reversible, thus emphasizing that epigenetic modifications may contribute to EMT plasticity, which could allow cancer cells to switch back to the epithelial state on colonization at a secondary site.

  • Non-coding RNAs, and in particular microRNAs (miRNAs), are master regulators of gene expression in many biological and pathological processes. Several miRNAs are able to influence the cellular phenotype through the suppression of genes that are involved in controlling the epithelial and mesenchymal cell states. Moreover, feedback loops with transcriptional regulators of EMT further define and/or maintain a given cellular state.

  • Alternative splicing of mRNA precursors leads to the formation of different proteins from the same gene, and this directs distinct physiological functions. EMT-associated alternative splicing events are regulated by several recently identified proteins, adding a new layer to the complex regulation of EMT.

  • More recent studies have indicated that protein levels of EMT-inducing transcription factors are tightly controlled by additional mechanisms. A first level of control is found at the point of translation initiation and elongation. A complex machinery determines the stability, subcellular localization and functionality of the proteins. Misregulation of translation and post-translational regulation may contribute to EMT in cancer cells.

Abstract

Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability.

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Figure 1: Role of EMT during cancer progression.
Figure 2: EMT is controlled by four major interconnected regulatory networks.
Figure 3: EMT is controlled by differential splicing events.

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Acknowledgements

The authors apologize to those colleagues whose relevant studies were not cited here. The authors' research is funded by grants from the VIB; the Fonds Wetenschappelijk Onderzoek, the geconcerteerde onderzoeksacties of Ghent University, Belgium; the Stichting tegen Kanker; the Association for International Cancer Research, UK; and the EU-FP7 framework program TuMIC 2008–201662.

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Glossary

E-cadherin

This protein is a classical cadherin. Cadherin cytoplasmic domains interact with a catenin-based complex, which couples to the actin cytoskeleton and regulates adhesion-dependent signalling. Loss of function may contribute to cancer progression by increasing proliferation, invasion and/or metastasis.

Mesenchymal to epithelial transition

(MET). The conversion of non-polarized and motile mesenchymal cells into polarized epithelial cells. MET is typically associated with increased E-cadherin levels and low cancer cell invasion and metastasis. It is the reverse of epithelial to mesenchymal transition.

Vimentin

Intermediate filament found in various non-epithelial cells, particularly mesenchymal cells.

Polycomb group proteins

Proteins first described in Drosophila melanogaster that are required for normal development. They work in multi-protein complexes, called Polycomb repressive complexes, that establish regions of chromatin in which gene expression is repressed.

Deamination of trimethylated H3K4

Methylation of lysine 4 (K4) in histone H3 has been linked to active transcription and is removed by LSD1 and the Jumonji C domain-containing proteins by amino oxidation or hydroxylation, respectively. The deamination catalysed by LOXL2 is a novel chemical mechanism for H3K4me3 modification.

Transforming growth factor-β

(TGFβ). TGFβ family members are potent extracellular factors that can initiate and maintain EMT in various biological systems. Adding TGFβ to epithelial cells in culture is a convenient way to induce EMT in various epithelial cells.

EMT-associated stem cell phenotypes

Cells undergoing EMT acquire motility and stemness phenotypes. Both traits are believed to form the basis for dissemination and metastasis of differentiated carcinomas, as the plasticity allows permanent adaptations to the demanding conditions of a changing environment.

Exon junction arrays

Microarrays constructed to measure the expression of alternative splice forms of a gene. The probes used are specific for expected or potential splice sites of predicted gene exons.

Cap-independent translation

The internal ribosome entry site (IRES) in the mRNA 5′ untranslated region is used for translation initiation. Cap-independent mRNAs can bypass translation inhibition when subjected to stresses such as hypoxia, and some mRNAs can use both the cap and IRES.

Ribosomal A site

During elongation cycles of translation each aminoacyl-tRNA enters the ribosome at the A site where the match is tested for the tRNA anti-codon with the codon of the mRNA, and where the amino end of its amino acid is transferred to the carboxylic end of the nascent chain.

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Craene, B., Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13, 97–110 (2013). https://doi.org/10.1038/nrc3447

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