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.
Nature communications. 2023 Aug 03*** epublish ***
Donglin Ding, Alexandra M Blee, Jianong Zhang, Yunqian Pan, Nicole A Becker, L James Maher, Rafael Jimenez, Liguo Wang, Haojie Huang
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA., Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA., Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA. ., Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, 55905, USA. .