Regulation of epithelial-mesenchymal transition through epigenetic and post-translational modifications

Abstract

The epithelial to mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal phenotype with invasive capacities. This phenomenon has been well documented in multiple biological processes including embryogenesis, fibrosis, tumor progression and metastasis. The hallmark of EMT is the loss of epithelial surface markers, most notably E-cadherin, and the acquisition of mesenchymal markers including vimentin and N-cadherin. The downregulation of E-cadherin during EMT can be mediated by its transcriptional repression through the binding of EMT transcription factors (EMT-TFs) such as SNAIL, SLUG and TWIST to E-boxes present in the E-cadherin promoter. Additionally, EMT-TFs can also cooperate with several enzymes to repress the expression of E-cadherin and regulate EMT at the epigenetic and post- translational level. In this review, we will focus on epigenetic and post- translational modifications that are important in EMT. In addition, we will provide an overview of the various therapeutic approaches currently being investigated to undermine EMT and hence, the metastatic progression of cancer as well.

Fig. 1

Changes in the molecular markers during EMT. E-cadherin, Desmoplakin, β-catenin and α-catenin are cell-cell contact proteins that are lost during EMT. N-cadherin, Vimentin, Fibronectin, SNAIL, Slug and Twist are mesenchymal markers that are gained during EMT

Fig. 2

Hydroxylation of HIF1A. In the presence of oxygen, HIF-1α is hydroxylated by PHD2. This hydroxylation is recognized by a protein complex containing Cullin 2, VHL, Elongin B, and Elongin C that targets HIF-1α for ubiquitination and leads to proteasome degradation of HIF1α. During EMT, the activation of TGF β decreases transcription of PHD2, which leads to the stabilization of HIF-1α. The stabilized HIF-1α binds to the hypoxia-response element (HRE) of the TWIST promoter along with HIF-1β to induce its transcription. (Blue arrowhead indicates sequential patterns. indicates inhibition. Purple arrowhead indicates translocation.)

Fig. 3

Phosphorylation of SNAIL and Par6. (Blue arrowhead indicates sequential patterns. indicates inhibition. Purple arrowhead indicates translocation.) a. SNAIL phosphorylation that suppresses EMT. GSK-3β phosphorylates SNAIL at two consecutive motifs. First, the phosphorylation at the second motif induces the cytoplasmic translocation of SNAIL from the nucleus. In the cytoplasm, SNAIL is phosphorylated on motif 1, and this phosphorylation is recognized by β-Trcp which targets it for proteosomal degradation of SNAIL. PKD1 is another kinase that phosphorylates SNAIL so it can be recognized by β-Trcp and FOXO11 that target it for proteosomal degradation. b. Mechanisms of EMT activation mediated by TGFβR. The activation of TGFβR results in the phosphorylation of Par6, and in turn activation of SMURF1 that targets RHOA degradation by the proteasome, which contributes to the disassembly of the tight junctions

Fig. 4

SUMOylation of SIP1 and FoxM1. (Blue arrowhead indicates sequential patterns. indicates inhibition.) a. Sumoylation of FOXM1 represses the expression of miR-200b/c, which normally acts as a tumor suppressor and reduces the expression of transcription factors ZEB1 and ZEB2.As a consequence epithelial phenotype is inhibited. b. Sumoylation of SIP1 decreases its transcription, which in turn prevents recruitment of CtBP to E-cadherin promoter. As a consequence, CtBP cannot prevent E-cadherin expression, which results in the maintenance of the expression of epithelial genes

Fig. 5

SNAIL Glycosylation. SNAIL is subject to O-linked glycosylation under hyperglycemic conditions. Consequently, the O-GlcNAc SNAIL promotes EMT by translocating it to the nucleus to bind to the E-cadherin promoter. (Purple arrowhead indicates translocation.)