Loss of peptidase D binding restores the tumor suppressor functions of oncogenic p53 mutants

Yang et al. report a mechanism of restoration of tumor suppressor activity of mutant p53 by disrupting its binding to peptidase D, leading to posttranslational modification, refolding and reactivation of the protein and its inhibition of cancer cell growth in vivo and in vitro. This finding presents a new possibility of reactivating mutant p53 and reveals a new therapeutic approach for a large number of human tumors. Tumor suppressor p53, a critical regulator of cell fate, is frequently mutated in cancer. Mutation of p53 abolishes its tumor-suppressing functions or endows oncogenic functions. We recently found that p53 binds via its proline-rich domain to peptidase D (PEPD) and is activated when the binding is disrupted. The proline-rich domain in p53 is rarely mutated. Here, we show that oncogenic p53 mutants closely resemble p53 in PEPD binding but are transformed into tumor suppressors, rather than activated as oncoproteins, when their binding to PEPD is disrupted by PEPD knockdown. Once freed from PEPD, p53 mutants undergo multiple posttranslational modifications, especially lysine 373 acetylation, which cause them to refold and regain tumor suppressor activities that are typically displayed by p53. The reactivated p53 mutants strongly inhibit cancer cell growth in vitro and in vivo. Our study identifies a cellular mechanism for reactivation of the tumor suppressor functions of oncogenic p53 mutants.

Automated summary

Yang et al. discovered a mechanism to reactivate mutant p53 as a tumor suppressor by disrupting its binding to peptidase D, leading to posttranslational modifications, refolding, and restoration of tumor suppressor activities. This finding suggests a new therapeutic approach for a wide range of human tumors by inhibiting cancer cell growth through the reactivation of mutant p53's tumor suppressor functions.