Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions

Abstract

Epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), play important roles in embryogenesis, stem cell biology, and cancer progression. EMT can be regulated by many signaling pathways and regulatory transcriptional networks. Furthermore, post-transcriptional regulatory networks regulate EMT; these networks include the long non-coding RNA (lncRNA) and microRNA (miRNA) families. Specifically, the miR-200 family, miR-101, miR-506, and several lncRNAs have been found to regulate EMT. Recent studies have illustrated that several lncRNAs are overexpressed in various cancers and that they can promote tumor metastasis by inducing EMT. MiRNA controls EMT by regulating EMT transcription factors or other EMT regulators, suggesting that lncRNAs and miRNA are novel therapeutic targets for the treatment of cancer. Further efforts have shown that non-coding-mediated EMT regulation is closely associated with epigenetic regulation through promoter methylation (e.g., miR-200 or miR-506) and protein regulation (e.g., SET8 via miR-502). The formation of gene fusions has also been found to promote EMT in prostate cancer. In this review, we discuss the post-transcriptional regulatory network that is involved in EMT and MET and how targeting EMT and MET may provide effective therapeutics for human disease.

Figure 1

Regulatory network in EMT and MET. EMT can be regulated by many signaling pathways, transcription factors, and post-transcriptional mechanisms.

Figure 2

MiRNA-regulating signaling pathways and transcription factors are involved in EMT. MiRNA influences EMT by targeting ligands, receptors, signaling pathways and transcription factors.

Figure 3

MiR-200 and miR-506 DNA methylation genomic loci and promoters of E- and N-cadherin. A. Graphical depiction of the miR-200b ~ 429 and miR-200c ~ 141 genomic loci, with putative transcription start sites (TSS) indicated by arrows. ZEB1 and Twist1 bound the E-box consensus in the promoters proximal to the putative miR-200 TSS and repressed miR-200 expression. The genomic position of miR-506 and five candidate methylation-regulated positions are also shown. B. SET8 interacted with Twist to regulate E-cadherin or N-cadherin promoter. MiR-502 suppressed SET8 directly and promoted E-cadherin expression.

Figure 4

MiRNA-gene network involved in EMT. The miRNA-gene network shows the eight key miRNA and EMT signature genes that are predicted to be regulated. This figure is modified from one in a Cancer Cell journal paper [72].