Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant
Jingwen Jiang, Hai‐Ning Chen, Ping Jin, Li Zhou, Liyuan Peng, Zhao Huang, Siyuan Qin, Bowen Li, Hui Ming, Maochao Luo, Na Xie, Wei Gao, Edouard C. Nice, Qiang Yu, Canhua Huang
Abstract
Abstract The single-nucleotide polymorphism (SNP) of p53, in particular the codon 72 variants, has recently been implicated as a critical regulator in tumor progression. However, the underlying mechanism remains elusive. Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation. Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant (but not p53 72R ) with phosphoserine aminotransferase 1 (PSAT1). Interestingly, p53 72P -PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) that otherwise bound to p53 72P , leading to subsequent nuclear translocation of PGC-1α and activation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Depletion of PSAT1 restored p53 72P -PGC-1α interaction and impeded the OXPHOS and TCA function, resulting in mitochondrial dysfunction and metastasis suppression. Notably, pharmacological targeting the PSAT1-p53 72P interaction by aminooxyacetic acid (AOA) crippled the growth of liver cancer cells carrying the p53 72P variant in both in vitro and patient-derived xenograft models. Moreover, AOA plus regorafenib, an FDA-proved drug for hepatocellular carcinoma and colorectal cancer, achieved a better anti-tumor effect on tumors carrying the p53 72P variant. Therefore, our findings identified a gain of function of the p53 72P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p53 72P -PSAT1 perturbation.