Role of Transcriptional Corepressor CtBP1 in Prostate Cancer Progression

转录辅阻遏物 CtBP1 在前列腺癌进展中的作用

• 批准号: 8458062
• 负责人: Sooryanarayana Varambally
• 金额: $ 30.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458062
• 关键词: Binding; Binding Proteins; Biological; Biological Markers; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Cell Proliferation; Cell Survival; Cell physiology; Cessation of life; Clinical; Clinical Management; Cytoplasm; Cytosol; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disseminated Malignant Neoplasm; EZH2 gene; Early Diagnosis; Enzymes; Etiology; Event; Failure; Gene Expression Profiling; Genes; Genetic; Histones; Hormonal; In Vitro; Lesion; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Molecular; Neoplasm Metastasis; Normal Cell; Oncogenic; Operative Surgical Procedures; Outcome; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prognostic Marker; Proteins; Role; Second Primary Cancers; Sum; Testing; Therapeutic Intervention; Time; Transcription Repressor/Corepressor; Tumor Cell Invasion; United States; Validation; Work; advanced disease; aggressive therapy; cancer cell; cohort; gene repression; hormone refractory prostate cancer; in vivo; inhibitor/antagonist; insight; men; novel; outcome forecast; overexpression; prostate cancer cell; stem; success; therapeutic target; transcription factor; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer and the second leading cause of cancer death for men in the United States. The molecular etiology of this disease varies widely and current therapies have a significant failure rate for advanced metastatic disease. A better understanding of the underlying molecular events that regulate prostate cancer progression will significantly enhance our ability to more accurately diagnose, classify and treat prostate cancer patients. By examining the molecular pathways that are dysregulated in cancer cells compared to normal cells, we can identify the specific genetic lesions that drive cancer progression. These genetic lesions can then be targets for appropriate therapies, either with existing compounds or inform the development of novel drugs. Our initial work found that the transcriptional corepressor CtBP1 is overexpressed in aggressive prostate cancer and data suggest that CtBP1 is required for prostate cancer cell survival. Loss of CtBP1 in cancer cells inhibits cell proliferation and invasion in vitro as well as metastasis in vivo. These observations indicate that prostate cancer cells may be critically dependent on CtBP1 for survival. The underlying hypothesis of this study is that CtBP1 may be an important biomarker for aggressive prostate cancer at the time of diagnosis that could impact the clinical management of patients. Being a functional dehydrogenase enzyme, CtBP1 serves as a viable therapeutic target in cancer and inhibition of CtBP1 activity by existing or novel compounds can potentially be used to effectively treat sub-sets of prostate cancer patients. The specific aims of this proposal are: Aim 1. Characterize CtBP1 expression and localization in prostate cancer. The expression of CtBP1 will be evaluated in a large cohort of prostate cancers to test the utility of CtBP1 expression as a diagnostic and prognostic marker. Aim 2. Evaluate the functional role of CtBP1 in aggressive prostate cancer. This aim will provide insight into the role of CtBP1 in prostate cancer progression. In addition, this aim will provide possible avenue to target CtBP1 for therapeutic interventions. Aim 3. Identify and characterize binding partners and targets of CtBP1 that play a role in prostate cancer progression. A sub aim here will focus on identification CtBP1 binding proteins that may be essential for CtBP1 activity and identify cellular proteins that target CtBP1 to the cytosol. Additionally, we will evaluate the genes regulated by CtBP1 followed by biological validation with an emphasis on therapeutically relevant targets. In sum, this proposal will investigate CtBP1 expression and cellular localization as well as determine its functional role in tumor invasion and metastasis. Proposal also identifies the binding partners and downstream targets of CtBP1. Additionally, we will investigate its clinical potential in the diagnosis and prognosis of prostate cancer, and we anticipate that uncovering CtBP1's role in prostate cancer will aid in the identification and/or development of potential inhibitor for treatment.

描述（由申请人提供）：前列腺癌是美国最常见的癌症，也是男性癌症死亡的第二大原因。这种疾病的分子病因学变化很大，目前的治疗方法对晚期转移性疾病有显著的失败率。更好地了解调节前列腺癌进展的潜在分子事件将显着提高我们更准确地诊断，分类和治疗前列腺癌患者的能力。通过检查与正常细胞相比在癌细胞中失调的分子通路，我们可以确定驱动癌症进展的特定遗传病变。然后，这些遗传病变可以成为适当疗法的目标，无论是使用现有化合物还是为新药的开发提供信息。我们的初步工作发现，转录辅抑制因子CtBP 1在侵袭性前列腺癌中过表达，数据表明CtBP 1是前列腺癌细胞存活所必需的。癌细胞中CtBP 1的缺失抑制了体外细胞增殖和侵袭以及体内转移。这些观察结果表明，前列腺癌细胞的生存可能严重依赖于CtBP 1。这项研究的基本假设是，CtBP 1可能是诊断时侵袭性前列腺癌的重要生物标志物，可能影响患者的临床管理。作为一种功能性脱氢酶，CtBP 1在癌症中充当可行的治疗靶标，并且通过现有或新型化合物抑制CtBP 1活性可潜在地用于有效治疗前列腺癌患者的亚组。本提案的具体目标是：目标1。表征前列腺癌中CtBP 1的表达和定位。CtBP 1的表达将在一个大的前列腺癌队列中进行评估，以测试CtBP 1表达作为诊断和预后标志物的效用。目标2.评估CtBP 1在侵袭性前列腺癌中的功能作用。这一目标将提供深入了解CtBP 1在前列腺癌进展中的作用。此外，这一目标将为靶向CtBP 1进行治疗干预提供可能的途径。目标3.鉴定和表征在前列腺癌进展中发挥作用的CtBP 1的结合伴侣和靶点。本文的一个子目标将集中于鉴定可能对CtBP 1活性至关重要的CtBP 1结合蛋白，并鉴定将CtBP 1靶向细胞溶质的细胞蛋白。此外，我们将评估CtBP 1调控的基因，然后进行生物学验证，重点是治疗相关的靶点。总之，本研究将探讨CtBP 1的表达和细胞定位，以及确定其在肿瘤侵袭和转移中的功能作用。提案还确定了CtBP 1的结合伙伴和下游靶点。此外，我们将研究其在前列腺癌诊断和预后中的临床潜力，我们预计揭示CtBP 1在前列腺癌中的作用将有助于识别和/或开发潜在的治疗抑制剂。