2. Academic Validation
  3. Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant

Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant

  • Signal Transduct Target Ther. 2023 Feb 15;8(1):65. doi: 10.1038/s41392-022-01266-7.
Jingwen Jiang # 1 2,  Hai-Ning Chen # 3,  Ping Jin # 1 2,  Li Zhou 1,  Liyuan Peng 1,  Zhao Huang 1,  Siyuan Qin 1,  Bowen Li 1,  Hui Ming 2,  Maochao Luo 1 2,  Na Xie 2,  Wei Gao 2,  Edouard C Nice 4,  Qiang Yu 5,  Canhua Huang 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China.
  • 2 West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China.
  • 3 Colorectal Cancer Center, Department of General Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
  • 4 Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
  • 5 Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Biopolis, Singapore, 138672, Singapore.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P.R. China. hcanhua@hotmail.com.
  • 7 West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, P.R. China. hcanhua@hotmail.com.
  • # Contributed equally.
PMID: 36788227 DOI: 10.1038/s41392-022-01266-7
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 p5372R) with phosphoserine aminotransferase 1 (PSAT1). Interestingly, p5372P-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) that otherwise bound to p5372P, leading to subsequent nuclear translocation of PGC-1α and activation of Oxidative Phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Depletion of PSAT1 restored p5372P-PGC-1α interaction and impeded the OXPHOS and TCA function, resulting in mitochondrial dysfunction and metastasis suppression. Notably, pharmacological targeting the PSAT1-p5372P interaction by aminooxyacetic acid (AOA) crippled the growth of liver Cancer cells carrying the p5372P 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 p5372P variant. Therefore, our findings identified a gain of function of the p5372P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p5372P-PSAT1 perturbation.

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