Arsenic Trioxide Reactivates Proteasome-Dependent Degradation of Mutant p53 Protein in Cancer Cells in Part via Enhanced Expression of Pirh2 E3 Ligase

摘要: The p53 gene is mutated in more than 50% of human tumors. Mutant exerts an oncogenic function and often highly expressed cancer cells due to evasion proteasome-dependent degradation. Thus, reactivating degradation mutant protein attractive strategy for management. Previously, we found that arsenic trioxide (ATO), a drug acute promyelocytic leukemia, degrades through proteasome pathway. However, it remains unclear what the E3 ligase targets In current study, sought identify necessary ATO-mediated p53. We ATO induces expression Pirh2 at transcriptional level. also knockdown inhibits, whereas ectopic enhances, ATO-induced protein. Furthermore, physically interacts with polyubiquitination subsequently proteasomal Interestingly, cooperates HSP90 or HDAC inhibitor promote growth suppression tumor cells. Together, these data suggest promotes part via induction Pirh2-dependent