Gain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis

Donglin Ding, Alexandra M. Blee, Jianong Zhang, Yunqian Pan, Nicole A. Becker, L. James Maher, Rafael Jimenez, Liguo Wang () and Haojie Huang ()
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Donglin Ding: Mayo Clinic College of Medicine and Science
Alexandra M. Blee: Mayo Clinic College of Medicine and Science
Jianong Zhang: Mayo Clinic College of Medicine and Science
Yunqian Pan: Mayo Clinic College of Medicine and Science
Nicole A. Becker: Mayo Clinic College of Medicine and Science
L. James Maher: Mayo Clinic College of Medicine and Science
Rafael Jimenez: Mayo Clinic College of Medicine and Science
Liguo Wang: Mayo Clinic College of Medicine and Science
Haojie Huang: Mayo Clinic College of Medicine and Science

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.

Date: 2023
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DOI: 10.1038/s41467-023-40352-4

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