TMPRSS2-ERG and gain-of-function p53 mutants co-dictate pyrimidine synthesis and prostate cancer fitness [RNA-seq-2018 ERG-p53 project]

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 beta-Catenin. Overexpressed ERG and beta-Catenin co-occupied PSG loci and mediated PSG expression, and high PSG expression associated with increased beta-Catenin level and poor overall survival of PCa patients. beta-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 beta-Catenin and pyrimidine synthesis in p53-mutated cancers with or without TMPRSS2-ERG fusion. To find the genes differentially expressed in Pb-ERG;Trp53pcR172H/- miceTMPRSS2-ERG融合基因（TMPRSS2-ERG fusion）是前列腺癌（prostate cancer, PCa）中最常见的遗传改变，TP53则是人类癌症中突变频率最高的基因。然而，二者在前列腺癌发病进程中的精确作用仍有待阐明。本研究证实，在前列腺癌患者标本中，TMPRSS2-ERG融合基因与TP53缺失/突变事件共同存在。在小鼠模型中，ERG过表达联合Trp53敲除/R172H突变敲入可诱导嘧啶合成基因（pyrimidine synthesis gene, PSG）的表达，并诱发前列腺肿瘤发生。功能获得型p53突变体可结合CTNNB1启动子并上调β-连环蛋白（beta-Catenin）的表达水平。过表达的ERG与β-连环蛋白共同占据PSG基因座并介导其转录，而高PSG表达与前列腺癌患者体内升高的β-连环蛋白水平及不良总生存期显著相关。通过靶向其辅助激活因子CBP及伴侣蛋白LEF1/TCFs的蛋白水解靶向嵌合体（proteolysis-targeting chimeras, PROTACs）抑制β-连环蛋白，可阻断ERG/p53突变型前列腺癌的增殖生长。本研究明确了CTNNB1是功能获得型p53突变体的转录靶点，并揭示了在携带或不携带TMPRSS2-ERG融合的p53突变癌症中，靶向β-连环蛋白与嘧啶合成存在可药用的治疗依赖性。本研究旨在筛选Pb-ERG;Trp53^(pcR172H/-)小鼠体内的差异表达基因。