Evaluating The Transcriptional Regulation of Cdh1 by Grhl3 in Different Cellular Models

Abstract

The calcium-dependent adhesion protein E-cadherin encoded by the Cdh1 gene is a member of a large family conferring proper establishment of adherens junction. The expression of Cdh1 is critical and is observed in epithelial cells. E-cadherin expression is also essential for establishing the pluripotent state in embryonic stem cells. Cdh1 transcriptional regulation has been the focus of research for many years; early reports identified repressors of Cdh1 since its downregulation is essential for the initiation of the epithelial to mesenchymal transition. Restoring the expression of Cdh1 is thought to be simply due to the disengagement of Cdh1 silencers from its promoter. Recent studies supported the presence of dedicated activators of Cdh1 expression, including members of the Grhl and Ets family of transcription factors. Here we evaluated the regulatory potential of Grhl3 on the Cdh1 promoter in different cellular models to understand the extent of the transcriptional relationship with Cdh1. We utilized several approaches, such as the correlation of expression by loss and gain of function, ChIP, and luciferase reporter assays. As a result, we found that Grhl3 is a potent regulator of Cdh1 in cells of epithelial origin. Moreover, Grhl3 was sufficient to re-establish Cdh1 expression in the murine hepatoma cells Hepa1-6. Improved understanding of the regulation of Cdh1 is essential for the perception of how the epithelial to mesenchymal and the mesenchymal to epithelial transitions are regulated, as they play a crucial role in metastasis, which will pave the way for better management of the metastatic disease.