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

Abstract

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.Epigenomes 2019, 3, 1 2 of 21 the digestion of the extracellular matrix and then to the escape of the primary tumor and the migration through the blood or lymphatic circulation [4,5].All the changes occurring during EMT at the morphological, functional, or molecular levels can be reversed to return to the original epithelial phenotype. This phenomenon is called mesenchymal to epithelial transition (MET) [8,9]. Through this process, circulating cancer cells can invade another organ, leading to the formation and growth of a secondary tumor called metastasis (Figure 1). However, the definition of EMT remains complex since there is not only one EMT but a multitude of intermediate states presenting different expressions of epithelial and mesenchymal markers. This plasticity has been described to be mainly linked to the epigenetic regulation of EMT, which is itself a highly plastic and reversible process, as described below.the overexpression of the immune checkpoint inhibitor PD-L1 (programmed death ligand 1) [1][2][3], and in metastasis formation [4,5]. Indeed, in type III EMT, tumor cells have been shown to present a loss of expression of adhesion proteins [6], to secrete various metalloproteases, such as MMP9 or ADAM19 [7], leading to the digestion of the extracellular matrix and then to the escape of the primary tumor and the migration through the blood or lymphatic circulation [4,5].All the changes occurring during EMT at the morphological, functional, or molecular levels can be reversed to return to the original epithelial phenotype. This phenomenon is called mesenchymal to epithelial transition (MET) [8,9]. Through this process, circulating cancer cells can invade another organ, leading to the formation and growth of a secondary tumor called metastasis (Figure 1). Howev...

EZH2 regulates oncomiR-200c and EMT markers in esophageal squamous cell carcinomas

“…Tumor metastasis and cell migration modulated by the epithelial mesenchymal transition (EMT) pathway are important in the development of various cancers 38 . Since many aggressive tumors were reported to overexpress EZH2, it was suggested that this protein act as an important regulator of the development of EMT 39 . Consistent with the previous prediction with web-based bioinformatics, we examined the mRNA level of the EMT genes in EZH2-treated YM-1 and KYSE-30 cells.…”

Unresolved Complexity in the Gene Regulatory Network Underlying EMT

“…Like EMT, epigenetic modifications-such as DNA or histone methylation, and histone acetylation-are also reversible, and have been shown to play a pivotal role in EMT regulation, which makes them attractive targets for novel chemotherapeutics (12). Interactions between key EMT transcription factors and enzymes that modify DNA/histones have been reviewed in detail (3,10,13,14).…”

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

“…Both EZH2 and KDM6B, two proteins with opposite catalytic activities, have previously been associated with cancer aggressiveness or EMT. Indeed, a high expression of EZH2 was associated with metastasis and a poor clinical outcome in clear cell renal cell carcinoma, esophagus squamous cell carcinoma, bladder urothelial carcinoma, cutaneous melanoma, hormone-refractory and metastatic prostate cancer, gastric carcinoma, breast carcinoma, lung carcinoma and ovarian carcinoma, as well as in pediatric brain tumors (for a review, see Lachat et al [21]). However, KDM6B expression has also been correlated with metastasis in clear cell renal cell carcinoma, ovarian cancer, myeloma, hepatocellular carcinoma, malignant pleural mesothelioma, and Hodgkin's lymphoma or invasive breast tumors.…”

“…Similarly, KDM6B, although far less studied, has been positively associated with EMT or metastasis in renal cancer or hepatocarcinoma [19,20]. Although these paradoxical roles have been recently discussed [21], it remains unclear how these proteins, with apparent opposite activities, could both promote EMT and/or cancer aggressiveness. To address this question, and in order to better understand the respective roles of EZH2 and KDM6B during EMT, we decided, for the first time, to simultaneously study these proteins in in vivo and in vitro models.…”