Epithelial to Mesenchymal Transition History: From Embryonic Development to Cancers.

Epithelial to mesenchymal transition (EMT) is a process that allows epithelial cells to progressively acquire a reversible mesenchymal phenotype. Here, we recount the main events in the history of EMT. EMT was first studied during embryonic development. Nowadays, it is an important field in cancer research, studied all around the world by more and more scientists, because it was shown that EMT is involved in cancer aggressiveness in many different ways. The main features of EMT's involvement in embryonic development, fibrosis and cancers are briefly reviewed here.

EZH2 and KDM6B Expressions Are Associated with Specific Epigenetic Signatures during EMT in Non Small Cell Lung Carcinomas.

The role of Epigenetics in Epithelial Mesenchymal Transition (EMT) has recently emerged. Two epigenetic enzymes with paradoxical roles have previously been associated to EMT, EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 (PRC2) Subunit), a lysine methyltranserase able to add the H3K27me3 mark, and the histone demethylase KDM6B (Lysine Demethylase 6B), which can remove the H3K27me3 mark. Nevertheless, it still remains unclear how these enzymes, with apparent opposite activities, could both promote EMT. In this study, we evaluated the function of these two enzymes using an EMT-inducible model, the lung cancer A549 cell line. ChIP-seq coupled with transcriptomic analysis showed that EZH2 and KDM6B were able to target and modulate the expression of different genes during EMT. Based on this analysis, we described INHBB, WTN5B, and ADAMTS6 as new EMT markers regulated by epigenetic modifications and directly implicated in EMT induction.

EMT is associated with an epigenetic signature of ECM remodeling genes.

Type III epithelial-mesenchymal transition (EMT) has been previously associated with increased cell migration, invasion, metastasis, and therefore cancer aggressiveness. This reversible process is associated with an important gene expression reprogramming mainly due to epigenetic plasticity. Nevertheless, most of the studies describing the central role of epigenetic modifications during EMT were performed in a single-cell model and using only one mode of EMT induction. In our study, we studied the overall modulations of gene expression and epigenetic modifications in four different EMT-induced cell models issued from different tissues and using different inducers of EMT. Pangenomic analysis (transcriptome and ChIP-sequencing) validated our hypothesis that gene expression reprogramming during EMT is largely regulated by epigenetic modifications of a wide range of genes. Indeed, our results confirmed that each EMT model is unique and can be associated with a specific transcriptome profile and epigenetic program. However, we could select some genes or pathways that are similarly regulated in the different models and that could therefore be used as a common signature of all EMT models and become new biomarkers of the EMT phenotype. As an example, we can cite the regulation of gene-coding proteins involved in the degradation of the extracellular matrix (ECM), which are highly induced in all EMT models. Based on our investigations and results, we identified ADAM19 as a new biomarker of in vitro and in vivo EMT and we validated this biological new marker in a cohort of non-small lung carcinomas.

Epigenetic Regulation of EMT (Epithelial to Mesenchymal Transition) and Tumor Aggressiveness: A View on Paradoxical Roles of KDM6B and EZH2.

EMT (epithelial to mesenchymal transition) is a plastic phenomenon involved in metastasis formation. Its plasticity is conferred in a great part by its epigenetic regulation. It has been reported that the trimethylation of lysine 27 histone H3 (H3K27me3) was a master regulator of EMT through two antagonist enzymes that regulate this mark, the methyltransferase EZH2 (enhancer of zeste homolog 2) and the lysine demethylase KDM6B (lysine femethylase 6B). Here we report that EZH2 and KDM6B are overexpressed in numerous cancers and involved in the aggressive phenotype and EMT in various cell lines by regulating a specific subset of genes. The first paradoxical role of these enzymes is that they are antagonistic, but both involved in cancer aggressiveness and EMT. The second paradoxical role of EZH2 and KDM6B during EMT and cancer aggressiveness is that they are also inactivated or under-expressed in some cancer types and linked to epithelial phenotypes in other cancer cell lines. We also report that new cancer therapeutic strategies are targeting KDM6B and EZH2, but the specificity of these treatments may be increased by learning more about the mechanisms of action of these enzymes and their specific partners or target genes in different cancer types.