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Gain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis.
- Source :
-
Nature communications [Nat Commun] 2023 Aug 03; Vol. 14 (1), pp. 4671. Date of Electronic Publication: 2023 Aug 03. - Publication Year :
- 2023
-
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.<br /> (© 2023. Springer Nature Limited.)
- Subjects :
- Animals
Humans
Male
Mice
beta Catenin genetics
beta Catenin metabolism
Gain of Function Mutation
Oncogene Proteins, Fusion genetics
Proto-Oncogenes
Pyrimidines biosynthesis
Prostatic Neoplasms genetics
Prostatic Neoplasms metabolism
Transcriptional Regulator ERG genetics
Transcriptional Regulator ERG metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 37537199
- Full Text :
- https://doi.org/10.1038/s41467-023-40352-4