Epigenetics of epithelial to mesenchymal transition (EMT) in cancer

Abstract Epithelial to Mesenchymal Transition (EMT) is an evolutionarily conserved developmental program that confers metastatic properties to cancer cells through the transformation of cells from the nonmotile and polarised epithelial state to a motile, nonpolarised mesenchymal state. EMT can impart higher invasion, stemness, and drug resistance to tumor cells and is usually involved in cancer cell dissemination. Its reverse—Mesenchymal to Epithelial Transition (MET) is often implicated in colonization—the last step of the metastatic cascade. Though several mechanisms of EMT induction and their phenotypic outcomes are well established, the dynamic reprogramming of the epigenome during EMT and/or MET and their influence on metastasis and drug resistance remains to be explored. This chapter will address several layers of epigenetic mechanisms such as DNA methylation, histone modifications, and their cross-talk that govern EMT and/or MET processes. The histone code regulating the activity of various EMT-associated transcription factors such as ZEB1, SNAIL, SLUG, TWIST1, and various MET-associated transcription factors such as GRHL2, as well as genome and epigenome-wide studies that have captured epigenetic signaling during EMT, would be presented. The rewiring of the epigenome during metabolic reprogramming and consequent EMT induction would be reviewed. The chapter will also highlight the role of epigenetic rewiring in mediating the reversibility (or lack thereof, i.e., irreversibility) of EMT/MET and the consequences of such changes during metastasis.