The Role of USP22 in Prostate Cancer Development and Progression

USP22 在前列腺癌发生和进展中的作用

• 批准号: 9920693
• 负责人: Jennifer Jones McCann
• 金额: $ 8.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-23 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920693
• 关键词: Address; Affect; Androgen Receptor; Automobile Driving; Binding; Biochemical; Biological Models; Biology; Bypass; Cancer Etiology; Cancer Patient; Cessation of life; Chromatin; Clinical; Complex; DNA Damage; Data; Development; Disease; Event; Fellowship; Genes; Genetic Transcription; Goals; Human; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Modeling; Nature; Oncogenes; Oncogenic; Organ; Outcome; Pathway interactions; Phase; Phenotype; Physiological; Prostate; Prostate Adenocarcinoma; Protein Deregulation; Receptor Signaling; Research; Research Project Grants; Role; SAGA; Sampling; Signal Transduction; Site-Directed Mutagenesis; TP53 gene; Therapeutic; Transcription Alteration; Transcription Regulatory Protein; Transcriptional Activation; Tumor Suppressor Proteins; United States; Up-Regulation; Work; androgen deprivation therapy; anticancer research; c-myc Genes; cancer initiation; cancer type; castration resistant prostate cancer; experience; genetic regulatory protein; genetic signature; genome-wide; human model; in vivo; interest; male; member; men; mouse model; novel; outcome forecast; overexpression; pre-doctoral; premature; programs; prostate cancer cell; prostate cancer progression; response; skills; standard of care; symposium; therapeutic target; transcriptome; translational cancer research; tumor; tumor progression

ABSTRACT Prostate cancer (PCa) is the second leading cause of cancer-related death for men in the United States. While organ-confined disease is manageable, advanced and disseminated PCa currently has no durable treatment options. Thus, understanding the causes and consequences of the transition from early stage to late stage castrate-resistant PCa (CRPC) are critical. While this transition has a requisite for androgen receptor (AR) activity, the mechanisms by which AR and other oncogenes are functionally increased, even after initial treatment with androgen deprivation therapy (ADT) have not been completely characterized. USP22, a known deubiquitinase associated with the SAGA transcriptional activation complex, was originally designated in a “death from cancer” gene signature. Importantly, USP22 is significantly upregulated in PCa patients with late-stage disease, and specifically indicates for poor outcome in PCa patients. Moreover, tumor-associated USP22 increases AR levels and activity as well as the c-MYC function, partially defining the mechanism by which tumor-associated USP22 drives PCa progression. Thus, while certain consequences of tumor-associated USP22 expression have been elucidated, the remaining downstream effects have not been thoroughly characterized. In this proposal, I will delineate the manner by which USP22 drives PCa development and progression. Specifically, I will describe the biochemical events controlled by USP22 that confer proliferation and survival on PCa cells, and furthermore I will define the role of tumor-associated USP22 on tumor development and therapeutic bypass in vivo. Moreover, I will expand on my ambition to continue studying transcriptional deregulation in cancer once I complete my predoctoral research.

摘要 前列腺癌(PCA)是美国男性癌症相关死亡的第二大原因。 虽然器官受限疾病是可控的，但晚期和播散性前列腺癌目前还没有持久的 治疗方案。因此，理解从早期阶段向 晚期抗去势PCa(CRPC)是关键。虽然这种转变对雄激素来说是必要的 受体(AR)活性，AR和其他癌基因功能增加的机制，甚至 经过最初的雄激素剥夺治疗(ADT)还没有完全确定。 USP22是一种已知的与sagA转录激活复合体相关的去泛素酶，最初是 被指定为“死于癌症”的基因签名。重要的是，USP22在PCa中显著上调 患有晚期疾病的患者，并特别提示PCa患者预后较差。此外， 肿瘤相关的USP22增加AR水平和活性以及c-myc功能，部分定义了 肿瘤相关的USP22推动前列腺癌进展的机制。因此，虽然某些后果 与肿瘤相关的USP22的表达已被阐明，其余的下游效应尚未被阐明 彻底刻画的。在本提案中，我将描述USP22驱动PCA的方式 发展和进步。具体地说，我将描述由USP22控制的生化事件 赋予前列腺癌细胞增殖和存活的能力，此外，我将定义肿瘤相关基因的作用 USP22关于体内肿瘤发展和治疗旁路的研究。此外，我将扩大我的雄心壮志 一旦我完成了我的博士前研究，就继续研究癌症中的转录去调控。