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.

Figure 1. The process of EMT and its reversible MET

Epithelial cells having a particular set of markers undergo biochemical changes and acquire different set of markers for a mesenchymal phenotype. ZO-1, zona occludens; MUC1, mucin 1; FOXC2, forkhead box C2.

Figure 2. SUPT16H, FACT subunit correlates with the epithelial phenotype in human intestinal cell lines

Analysis using data from Cancer Cell Line Encyclopedia indicates increased expression of epithelial markers for SUPT16H and decreased expression of mesenchymal markers in intestinal cell lines.

Figure 3. EMT-TFs interact with epigenetic regulators to repress epithelial genes

EMT inducing factors activate the EMT-TFs which in turn interact with epigenetic regulators to repress the expression of epithelial genes. PRC2, polycomb repressive complex 2; DNMT1, DNA methyltransferase 1; HDAC, histone deacetylase; CtBP, C-terminal binding protein; BMI1, B lymphoma Mo-MLV insertion region 1; SET, Su(var) 3-9, Enhancer of Zeste and Trithorax

Figure 4. Signaling activators induce transcription of EMT-TFs which in turn regulate histone modifications on target genes

Upon inducing signal, activating histone modifications on the genes of EMT-TFs promote transcription. EMT-TFs then interact with epigenetic regulators to mark the target genes for activation or repression.