Multilayer control of the EMT master regulators

Metastasis is the leading cause of cancer-associated death in most tumor types. Metastatic dissemination of cancer cells from the primary tumor is believed to be initiated by the reactivation of an embryonic development program referred to as epithelial-mesenchymal transition (EMT), whereby epithelial cells lose apicobasal polarity and cell-cell contacts, and gain mesenchymal phenotypes with increased migratory and invasive capabilities. EMT has also been implicated in the regulation of cancer stem cell property, immune suppression and cancer regression. Several transcription factors have been identified as master regulators of EMT, including the Snail, Zeb and Twist families, and their expression is tightly regulated at different steps of transcription, translation and protein stability control by a variety of cell-intrinsic pathways as well as extracellular cues. Here, we review the recent literature on the signaling pathways and mechanisms that control the expression of these master transcription factors during EMT and cancer progression.