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 ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 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 ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death.
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p53 ΔNp63 ΔNp63 ΔNp63 ΔNp63 Pirh2 ΔNp63 p63 TAp63 ΔNp63 arsenic TAp63 ΔNp63 ΔNp63 p53 ΔNp63 ΔNp63 TAp63 ΔNp63 proteasome ΔNp63 arsenic Pirh2 promoter Pirh2 Pirh2 Pirh2 Pirh2 ΔNp63 arsenic arsenic arsenic trioxide arsenic trioxide arsenic trioxide Arsenic Transcription factor p63