Cooperativity of TMPRSS2-ERG fusion with p53 inactivation in prostate cancer pathogenesis

TMPRSS2-ERG 融合与 p53 失活在前列腺癌发病机制中的协同作用

• 批准号: 10557878
• 负责人: Liewei Wang
• 金额: $ 48.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557878
• 关键词: Acceleration; Age; Age Months; American; Binding; CDK2 gene; Cancer Etiology; Cancer Patient; Cancerous; Cell Cycle Progression; Cells; Cessation of life; Chromatin; Code; Complex; Data; Development; Elderly; Epigenetic Process; Exons; Gene Deletion; Gene Expression; Gene Fusion; Gene Mutation; Gene Proteins; Gene Targeting; Genes; Genetic Transcription; KDM1A gene; Knock-out; Lesion; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Molecular; Molecular Mechanisms of Action; Mus; Mutation; N-terminal; Oncogene ETS; Oncogenic; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Precision therapeutics; Prostate; Prostate Cancer therapy; Prostatic Intraepithelial Neoplasias; Reader; Regulation; Role; Signal Pathway; Signal Transduction; Specimen; TMPRSS2 gene; TP53 Gene Inactivation; TP53 gene; Testing; Threonine; Transgenes; advanced prostate cancer; androgen sensitive; anti-cancer; clinically significant; demethylation; design; disorder subtype; effective therapy; genomic locus; men; molecular subtypes; next generation sequencing; novel; novel therapeutics; overexpression; programs; promoter; prostate cancer cell; prostate carcinogenesis; transcription factor; transcriptome

PROJECT SUMMARY Prostate cancer (PCa) is the second leading cause of cancer death in American men. The TMPRSS2-ETS related gene (ERG) fusion (termed T2-ERG), juxtaposing the strong androgen-responsive TMPRSS2 gene promoter with the coding region of the putative oncogene ERG, occurs in approximately 50% of all PCa in patients. It has been inferred that overexpressed truncated T2-ERG is a key player in PCa pathogenesis. Notably, a number of studies show that overexpression of T2-ERG protein alone is insufficient to trigger formation of PCa in mice unless at very advanced age (> 24 months), implying the requirement of additional lesions in T2-ERG overexpression-induced PCa pathogenesis. By analyzing the NGS data from > 1500 cases of PCa patient specimens, we showed that T2-ERG fusion and p53 inactivation (loss of p53 tumor suppressor function due to TP53 gene deletion and/or mutation) co-occurred in both primary and metastatic PCa, supporting the notion that T2-ERG fusion and TP53 inactivation cooperate to drive PCa pathogenesis and progression. We demonstrated that prostate-specific T2-ERG transgene and Trp53 knockout (T2-ERG+/p53-) not only largely enhanced ERG target gene expression, but also induced high-grade prostatic intraepithelial neoplasia (HGPIN) and cancerous lesions in mice at 12-15 months of age. Mechanistically, we identified LSD1 as a direct binding partner of ERG protein and showed that cyclin-dependent kinase-2 (CDK2) phosphorylates LSD1 at threonine 59 (T59-p), which disrupts LSD1 interaction with HP1γ, an epigenetic `reader' of H3K9me2/3 and induces demethylation of these transcription repressive chromatin marks at ERG target gene loci. Based on these novel preliminary data, we hypothesize that in p53-proficient cells the oncogenic potential of T2-ERG is constrained under a transcription repressive chromatin state through association with the LSD1-HP1γ complex. However, p53 inactivation induces loss or downregulated expression of p21WAF1, aberrant activation of CDKs and accelerated cell cycle progression, which in turn triggers LSD1 T59-p-mediated disassociation of HP1γ from LSD1, HP1γ eviction from chromatin due to accelerated cell cycle progression-associated H3S10 phosphorylation (H3S10-p), thereby promoting H3K9me demethylation at ERG target gene loci, oncogenic reprogramming of ERG transcriptome, and PCa pathogenesis and progression. To test this hypothesis, we will determine the molecular basis and regulation of LSD1 phosphorylation-mediated inhibition of LSD1-HP1γ interaction in T2-ERG+/p53- PCa cells (Aim 1), define the mechanism and extent to which LSD1 enzymatic activity and T59 phosphorylation regulates ERG transcriptional program in T2-ERG+/p53- PCa cells (Aim 2), and determine the clinical significance of the interplay between ERG and p53 signaling and anti-cancer efficacy of targeting LSD1 and ERG pathways in T2-ERG+/p53- PCa (Aim 3). Findings from the proposed studies will shed new light on molecular mechanisms of PCa pathogenesis and could lead to development of novel therapeutics for the treatment of T2-ERG+/p53- PCa.

项目摘要 前列腺癌（PCA）是美国男性癌症死亡的第二大原因。 TMPRSS2-ET 相关基因（ERG）融合（称为T2-ERG），并置强雄激素反应TMPRSS2基因 具有推定致癌基因ERG的编码区域的启动子，大约有50％的PCA中的50％ 患者。已经推断出过表达的截短的T2-erg是PCA发病机理的关键参与者。尤其， 许多研究表明，仅T2-erg蛋白的过表达不足以触发PCA的形成 在小鼠中，除非在非常高的年龄（> 24个月），这意味着在T2-erg中需要其他病变 过表达诱导的PCA发病机理。通过分析> 1500例PCA患者的NGS数据 标本，我们表明T2-erg融合和p53失活（由于p53肿瘤抑制功能的丧失 TP53基因缺失和/或突变）在原发性和转移性PCA中共发生，支持这样的观念 T2-ERG融合和TP53灭活合作，以驱动PCA发病机理和进展。我们证明了 前列腺特异性的T2-erg变换和TRP53敲除（T2-erg+/p53-）不仅在很大程度上增强了ERG 靶基因表达，但还诱导高级前列腺上皮内肿瘤（HGPIN）和取消 12-15个月大的小鼠病变。从机械上讲，我们将LSD1确定为ERG的直接结合伙伴 蛋白质并表明细胞周期蛋白依赖性激酶-2（CDK2）在苏氨酸59（T59-P）处磷酸化LSD1，这 破坏LSD1与HP1γ的相互作用，这是H3K9ME2/3的表观遗传学的“读取器”，并诱导这些脱甲基化 ERG靶基因基因座的转录反射染色质标记。基于这些新颖的初步数据，我们 假设在p53促进细胞中，T2-erg的致癌潜力受到转录的约束 通过与LSD1-HP1γ复合物相关的抑制性染色质状态。但是，p53失活会诱导 p21WAF1的丧失或下调表达，CDK的异常激活和加速的细胞周期进程， 这反过来触发HP1γ与LSD1的LSD1 T59-P介导的分离，从染色质驱逐HP1γ 由于加速的细胞周期进展相关H3S10磷酸化（H3S10-P），从而促进 ERG靶基因局部的H3K9ME去甲基化，ERG转录组的致癌重编程和PCA 发病机理和进展。为了检验这一假设，我们将确定分子基础和调节 LSD1磷酸化介导的抑制T2-erg+/p53- PCA细胞中LSD1-HP1γ相互作用（AIM 1），定义 LSD1酶活性和T59磷酸化调节ERG的机制和程度 T2-ERG+/p53- PCA细胞中的转录程序（AIM 2），并确定相互作用的临床意义 在T2-erg+/p53-中，ERG和p53信号传导和抗癌效率之间 PCA（目标3）。拟议研究的发现将为PCA的分子机制提供新的启示 发病机理，可能导致用于治疗T2-ERG+/p53- PCA的新型治疗。