ΔNp63α utilizes multiple mechanisms to repress transcription in squamous cell carcinoma cells

Delta Np63 alpha is a potent oncogene in squamous cell carcinomas (SCCs) and a pro-proliferative factor expressed by basal epithelial cells. Delta Np63 alpha functions both as a transcriptional repressor and activator, but it is not clear how these activities contribute to its oncogenic potential. Delta Np63 alpha was proposed to function as a dominant negative of the related factor p53. Additionally, Delta Np63 alpha was shown to inactivate its family member TAp73 and mediate recruitment of repressive histone deacetylase (HDAC) complexes to chromatin. Recently, we identified a new mechanism of repression involving recruitment of histone H2A/H2A.Z exchange complexes and H2A.Z deposition at Delta Np63 alpha target genes. Here, we aimed to define the possible co-occurrence of the various repressive mechanisms. In lung SCC cells expressing Delta Np63 alpha, p53 and TAp73, we found that Delta Np63 alpha exerts its pro-proliferative and transcriptional repressive effects in a manner independent of p53, TAp73 and histone H3 and H4 deacetylation. Instead, Delta Np63 alpha target genes are differentiated from non-target genes within the p53 network by incorporation and accumulation of acetylated H2A.Z. These results indicate that Delta Np63 alpha utilizes multiple mechanisms of repression in diverse epithelial and SCC cells.