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TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [ERG and p53 ChIP-seq]

ABSTRACT: TMPRSS2-ERG fusion is the most common genetic alteration in prostate cancer (PCa) and TP53 is the most frequently mutated gene in human cancers. However, their precise roles in PCa pathogenesis remain elusive. Here we showed that TMPRSS2-ERG fusion co-occurred with TP53 deletion/mutation in PCa patient specimens. ERG overexpression and Trp53 knockout/R172H mutant knockin induced pyrimidine synthesis gene (PSG) expression and prostate tumorigenesis in mice. Gain-of-function p53 mutants bound to the CTNNB1 promoter and upregulated β-Catenin. Overexpressed ERG and β-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased β-Catenin level and poor overall survival of PCa patients. β-Catenin inhibition by proteolysis-targeting chimeras (PROTACs) of its co-activator CBP and partner proteins LEF1/TCFs blocked ERG/p53-mutant PCa growth. Our study identifies CTNNB1 as a transcriptional target of p53 GOF-mutants, and reveals a druggable dependency on β-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184623 | GEO | 2023/06/27

REPOSITORIES: GEO

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Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen Test Cohort: 388 cases from the population based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Validation cohort: The PhysiciansM-bM-^@M-^Y Health Study (PHS) cohort included 116 US men diagnosed with incidental prostate cancer between 1983 and 2003; 455 cases were annotated for TMPRSS2-ERG fusion. Test Set: GSM208029 ... GSM208392 Validation Set: GSM208404 ... GSM208512

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TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [ERG and p53 ChIP-seq]

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