Architecture of epigenetic reprogramming following twist1-mediated epithelialmesenchymal transition

Epithelial-mesenchymal transition (EMT) is known to promote cellular plasticity during the formation of the mesoderm from epiblasts and the neural crest cells from the neural tube in the developing embryo as well as during adult wound healing [1]. During EMT, epithelial cells lose their epithelial characteristics and acquire mesenchymal morphology, which facilitates cellular dissociation and migration. Similar to embryo development, neoplastic cells have been shown to reactivate EMT leading to cancer metastasis [2]. Induction of EMT is also involved in the development of resistance to cytotoxic chemotherapy and targeted agents [3-5]. In addition, EMT imparts stem cell properties to differentiated cells [6]. Since cancer cells seem to acquire stem cell properties dynamically in response to the tumor microenvironment and become differentiated at distant sites, it has been suggested that major epigenetic remodeling would occur during EMT to facilitate metastasis. Although DNA methylation changes at specific loci have been established during EMT [7,8], changes in the global DNA methylation landscape are not well understood. Indeed, a recent report demonstrated that DNA methylation is largely unchanged during EMT mediated by transforming growth factor beta (TGF-β) [9], while another showed that EMT is associated with specific alterations of gene-related CpG-rich regions [10]. Moreover, another report showed a striking difference in DNA methylation in non-small cell lung cancers between mesenchymal-like tumors and epithelial-like tumors, which display a better prognosis and exhibit greater sensitivity to inhibitors of epidermal growth factor receptor [11].