Epigenetic plasticity: A central regulator of epithelial-to-mesenchymal transition in cancer

Abstract

Tumor metastasis is the major cause of mortality and morbidity in most solid cancers. A growing body of evidence suggests that the epithelial-to-mesenchymal transition (EMT) plays a central role during tumor metastasis and frequently imparts a stem cell-like phenotype and therapeutic resistance to tumor cells. The induction of EMT is accompanied by a dynamic reprogramming of the epigenome involving changes in DNA methylation and several post-translational histone modifications. These changes in turn promote the expression of mesenchymal genes or repress those associated with an epithelial phenotype. Importantly, in order for metastatic colonization and the formation of macrometastases to occur, tumor cells frequently undergo a reversal of EMT referred to as the mesenchymal-to-epithelial transition (MET). Thus, a high degree of epigenetic plasticity is required in order to induce and reverse EMT during tumor progression. In this review, we describe various epigenetic regulatory mechanisms employed by tumor cells during EMT and elaborate on the importance of the histone code in controlling both the expression and activity of EMT-associated transcription factors. We propose that a more thorough understanding of the epigenetic mechanisms controlling EMT may provide new opportunities which may be harnessed for improved and individualized cancer therapy based on defined molecular mechanisms.

Epigenetic Control of the Tumor Microenvironment

“…Certain chromatin complexes are involved in the post-translational modification (e.g., methylation, acetylation, ubiquitylation) of histones, leading to activation or suppression of transcription of specific genes [57,58]. The methylation of nucleosomal histones at specific lysine residues can either repress (e.g., H3K9me3, H3K27me3) or stimulate (e.g., H3K4me3) transcription.…”

“…Histone demethylases, which remove methyl groups from histones, also play active roles in regulating the epigenetic status of the cell [61]. Histone acetylation at specific lysines (e.g., H3K9, H3K36, H3K27) is accomplished by a large group of histone acetylases and is often associated with gene activation, whereas removal of these acetyl marks by histone deacetylases (HDACs) is linked to gene repression [57,[62][63].…”

Downregulation of miR-129-2 by promoter hypermethylation regulates breast cancer cell proliferation and apoptosis

“…The methylation of CpG islands in gene promoters has been strongly linked to the silencing of the expression of tumor-suppressor genes in different types of cancers (14)(15)(16)(17). The hypermethylation of promoter CpG islands has been found to affect not only tumor-suppressor mRNAs, but also tumor-suppressor miRNAs.…”

Cross-cell DNA methylation annotation and analysis for pan-cancer study

“…Together we seek to detect whether there exists any functional association (Szklarczyk et al, 2015) between those identified genes from hyper-DMRs and hypo-DMRs, which can explain the differential expression between those genes qualitatively, especially for the genes belonging to tumor suppressor genes (TSG) (Bedi et al, 2014;Blattler et al, 2014;Zhao et al, 2013). …”