Phospho-ΔNp63α/NF-Y protein complex transcriptionally regulates DDIT3 expression in squamous cell carcinoma cells upon cisplatin exposure

Cisplatin remains the most important chemotherapeutic agent for patients with human head and neck cancer. However, tumor cells often develop resistance to cisplatin-induced apoptosis. We previously found that head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin display a marked ATM-induced phosphorylation of ΔNp63?. However, the mutated Np63-S385G failed to undergo phosphorylation by ATM kinase. We used HNSCC cell lines expressing the wild type ΔNp63α or mutated ΔNp63α-S385G to determine the effect of S385G mutation on the ΔNp63α transcriptional activity and protein-protein interactions. The S385G mutation in ΔNp63α dramatically abolished the upregulation/ downregulation of downstream gene targets and the binding of ΔNp63α-S385G to certain promoters. In contrast to the non-phosphorylated ΔNp63α-S385G, the phospho-ΔNp63α forms protein-protein complexes with NF-YA transcription factor and regulates the transcription of DDIT3 gene implicated in the programmed cell death of HNSCC cells upon cisplatin exposure. We suggest that the transcriptional activation of ΔNp63α through its phosphorylation by ATM kinase in HNSCC cells exposed to cisplatin is a critical step in the subsequent sensitivity of certain human head and neck cancers to platinum therapy.