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-ETS 相关基因（ERG）融合（称为T2-ERG），并置强雄激素反应性TMPRSS 2基因 具有推定的癌基因ERG的编码区的启动子，在所有PCa中约50%的PCa中存在， 患者已经推断过表达的截短T2-ERG是PCa发病机制中的关键参与者。值得注意的是， 许多研究表明，T2-ERG蛋白单独过表达不足以触发PCa的形成， 在小鼠中，除非年龄很大（> 24个月），这意味着T2-ERG需要额外的病变 过表达诱导PCa发病机制。通过对1500例以上前列腺癌患者的NGS数据进行分析， 我们发现，T2-ERG融合和p53失活（p53肿瘤抑制功能的丧失， TP 53基因缺失和/或突变）同时发生在原发性和转移性PCa中，支持以下观点： T2-ERG融合和TP 53失活协同驱动PCa发病和进展。我们证明 前列腺特异性T2-ERG转基因和Trp 53敲除（T2-ERG+/p53-）不仅大大增强了ERG， 靶基因表达，但也诱导高级别前列腺上皮内瘤变（HGPIN）和癌 在12-15个月大的小鼠中的病变。从机制上讲，我们确定LSD 1是ERG的直接结合伴侣 细胞周期蛋白依赖性激酶2（CDK 2）磷酸化LSD 1的苏氨酸59（T59-p）， 破坏LSD 1与HP 1 γ的相互作用，HP 1 γ是H3 K9 me 2/3的表观遗传“阅读器”，并诱导这些蛋白的去甲基化。 在ERG靶基因位点的转录抑制染色质标记。根据这些新的初步数据，我们 假设在p53-熟练细胞中，T2-ERG的致癌潜力受到转录的限制， 通过与LSD 1-HP 1 γ复合物结合抑制染色质状态。然而，p53失活诱导 p21 WAF 1表达缺失或下调，CDK异常激活和细胞周期进程加速， 这反过来触发LSD 1 T59-p介导的HP 1 γ从LSD 1解离，HP 1 γ从染色质驱逐 由于加速的细胞周期进展相关的H3 S10磷酸化（H3 S10-p），从而促进 ERG靶基因位点的H3 K9 me去甲基化、ERG转录组的致癌重编程和PCa 发病机制和进展。为了验证这一假设，我们将确定 T2-ERG+/p53- PCa细胞中LSD 1磷酸化介导的LSD 1-HP 1 γ相互作用抑制（目的1），定义 LSD 1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（目的2），并确定相互作用的临床意义 ERG和p53信号传导与靶向T2-ERG+/p53-中LSD 1和ERG通路的抗癌功效之间的关系 PCa（目标3）。这些研究结果将为PCa的分子机制提供新的线索 这可能导致开发用于治疗T2-ERG+/p53- PCa的新疗法。