ZNF185 is a p63 target gene critical for epidermal differentiation and squamous cell carcinoma development.

Abstract

Development and maintenance of healthy stratified epithelia require the coordination of complex transcriptional programmes. The transcription factor p63, a member of the p53 family, plays a crucial role in epithelial development and homeostasis. Analysis of the p63-dependent transcriptome indicated that one important aspect of p63 functions in epithelial development is the regulation of cell-cell and cell-matrix adhesion programmes. However, limited knowledge exists on the relevant cell-cell adhesion molecules involved in physiological epithelial formation. Similarly, limited data are available to understand if deregulation of the cell-cell adhesion programme is important in tumour formation. Here, using the epidermis as an experimental model with the RNA sequencing approach, we identify a novel p63-regulated gene induced during differentiation, ZNF185. ZNF185 is an actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein, whose function is poorly known. We found that p63 binds to a specific enhancer region, promoting its expression to sustain epithelial differentiation. ZNF185 silencing strongly impaired keratinocyte differentiation according to gene array analysis. ZNF185 is detected at the cell-cell periphery where it physically interacts with E-cadherin, indicating that it is important to maintain epithelial integrity beyond its pro-differentiation role. Interestingly, poorly differentiated, including head and neck, cervical and oesophageal, squamous cell carcinomas display loss of ZNF185 expression. Together, these studies reinforce that p63 is a crucial gene for maintaining epithelial tissue integrity and support the deregulation of the cell-cell adhesion programme,which plays a critical role in carcinoma development.