Transcriptional control of late differentiation in human keratinocytes by TAp63 and Notch

We previously showed that in cervical carcinoma cells, the TAp63 beta isoform of the p63 transcription factor is negatively interfering with the carcinogenic pathways promoting anchorage-independent growth. In this study, we have defined the mechanisms underlying the effects of TAp63 beta through a transcriptome analysis of human keratinocytes overexpressing this protein. TAp63 beta modulated expression of 1203 genes (944 activated and 259 repressed; P-value <0.05), notably genes involved in epithelial development and keratinocyte differentiation. In comparison, while TAp63 gamma acts similarly to TAp63 beta to transactivate a selected panel of target genes, other p63 isoforms, including Delta Np63 alpha, which is highly expressed in keratinocytes, are inactive. Upon induction of differentiation of primary human keratinocytes, we observed endogenous expression of TAp63 beta and gamma isoforms, along with transcriptional activation of selected target genes. Intriguingly, our data also indicated that TAp63 beta activates transcription of members of the Notch pathway, which is known to promote keratinocyte differentiation. By inhibiting and activating the Notch pathway, we revealed a subset of TAp63 beta-activated genes that were co-dependent on Notch for their expression. Our work demonstrates that the shorter TAp63 isoforms (TAp63 beta/gamma) are specifically induced in human keratinocytes and cooperate with Notch signalling to activate transcription of late differentiation genes supporting their role as putative tumor suppressors in HPV-associated tumorigenesis.