Arsenic Suppresses Cell Survival via Pirh2-mediated Proteasomal Degradation of ΔNp63 Protein

Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and Delta Np63. Although TAp63 acts as a tumor suppressor, Delta Np63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting Delta Np63 might be used to manage tumors that overexpress Delta Np63. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits Delta Np63 but not TAp63 expression in time-and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of Delta Np63 protein via a proteasome-dependent pathway but has little effect on the level of Delta Np63 transcript. Furthermore, we found that arsenic trioxide activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of Delta Np63 protein. Importantly, we found that knockdown of Delta Np63 sensitizes, whereas ectopic expression of Delta Np63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades Delta Np63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of Delta Np63 expression facilitates tumor cells to arsenic-induced death.