Epigenetic regulation of epithelial cellular fate by CTBP

Abstract

Epithelial phenotype is a default state of epithelial cells. The shift between epithelial and mesenchymal phenotypes is one of the hallmarks of cancer. Epithelial cells retain incredible plasticity. They can differentiate and self‐renew during embryonic and post‐natal organ development. An essential developmental process is the ability to weaken their typical epithelial features and change to a mesenchymal state by activating epithelial to mesenchymal transition (EMT), a program that is abnormally activated during tumor progression and metastasis, yet is required for effective tissue repair. This plasticity has central implication for the dysregulation of epithelial and mesenchymal states that leads to cancer initiation and progression.C‐terminal binding protein (CTBP) is an epigenetic regulatory protein that controls gene expression in response to metabolic imbalance. It is activated in the presence of NADH to recruit and target a variety of histone modifying complexes and transcriptional regulators to chromatin, thus providing a defined network of interactions that modulate cellular programming. Recently, we have found that CTBP controls major cancer hallmark pathways including genome instability, EMT, and tumor initiating cells and stemness. In order to define the mechanisms through which CTBP controls cellular plasticity, we compared non‐tumorigenic human breast epithelial MCF10A cells with CTBP‐depleted MCF10A. Using this system, we characterized several molecular biological and biochemical properties driven by CTBP in correlation with genome‐wide profiling by ChIP‐Seq and RNA‐Seq.In this study we illustrate that CTBP depletion enhances epithelial differentiation and upregulates epithelial gene expression and CTBP overexpression shifts differentiation from epithelial to mesenchymal in mammary epithelial cells. Furthermore, we find that CTBP plays an important role in influencing epithelial plasticity mediated by DNA methylation inhibition, thus providing a conceivable opportunity for enhanced therapeutic intervention.