The primary role of low NCOA6 expression in the prostate cancer disparity among African American men

NCOA6 低表达在非裔美国男性前列腺癌差异中的主要作用

• 批准号: 10356340
• 负责人: JIANMING XU
• 金额: $ 22.44万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356340
• 关键词: Address; African American; American; Androgens; Binding; Biological Assay; Cancer Cell Growth; Castration; Cell model; Chromatin; Chromatin Conformation Capture and Sequencing; Chromatin Loop; Complex; Coupled; DNA-Protein Interaction; Data Analyses; Development; Diagnostic; Diet; Distant; Down-Regulation; EGFR Protein Overexpression; Enhancers; Epidermal Growth Factor Receptor; Epithelial; European; Event; Future; Genetic; Genetic Transcription; Growth; Hyperplasia; Immune response; Incidence; Knock-out; Knowledge; Letters; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Modeling; Molecular; Mus; Mutate; Mutation; NCOA6 gene; Nuclear Receptors; Oncogenic; Outcome; Outcome Study; Pathway interactions; Patients; Performance; Phase; Play; Prognosis; Prognostic Marker; Prostate; Prostatic; Proteins; Proto-Oncogenes; Regulation; Repression; Research; Resistance; Risk Factors; Role; SCID Mice; Site; Specimen; Testing; Tissue Microarray; Tissues; Transcription Coactivator; Work; Xenograft procedure; advanced prostate cancer; androgen sensitive; anticancer research; base; cancer health disparity; castration resistant prostate cancer; cell growth; chromatin immunoprecipitation; experimental study; gene network; high risk; inhibitor; intraepithelial; knock-down; men; mouse model; nuclear factor Y; overexpression; personalized medicine; prevent; promoter; prostate cancer cell; prostate cancer cell line; protein expression; receptor; receptor expression; receptor upregulation; recruit; targeted treatment; transcription factor; tumor xenograft

Project Summary/Abstract Comparing with European American (EA) men, African American (AA) men have significantly higher prostate cancer (PC) incidence, and their PCs are more likely to become castration-resistant, metastatic, and lethal. It is still unclear what causes this AA PC disparity. Overexpressed EGFR can be oncogenic, and EGFR is more frequently overexpressed in AA PCs compared with EA PCs, but it is still unknown what causes EGFR overexpression (OE). We found that NCOA6, a transcription coregulator with pleiotropic functions, is frequently downregulated in AA PCs, and its loss causes EGFR OE in AA PC cells. We also found that knockout (KO) of NCOA6 promotes prostate epithelial hyperplasia with heterozygous Pten to develop fast-growing, invasive, metastatic, lethal PCs in the mouse prostates. Based on these findings, we hypothesize that NCOA6 is more frequently downregulated in AA PCs versus EA PCs, and its frequent downregulation is associated with the frequent EGFR OE in aggressive AA PCs with poor prognosis. We also hypothesize that NCOA6 loss causes EGFR OE, which in turn promotes castration-resistant PC (CRPC) development. In Specific Aim 1, we plan to associate low NCOA6 expression with EGFR OE and CRPC development in AA PCs. Specifically, we will measure and compare NCOA6 and EGFR protein expression levels in both AA and EA PCs and matched adjacent normal prostate tissue specimens, and perform comprehensive data analysis. We hope to find higher percentage of AA PCs with low-NCOA6 and high-EGFR expression compared with EA PCs, which will connect the frequent NCOA6 downregulation to the development of AA PC disparity. We will also examine whether NCOA6 loss can promote androgen-sensitive AA PC cells to develop CRPCs, and whether NCOA6 loss- promoted CRPCs depend on EGFR OE to grow and survive. If successful, the outcomes of these studies will associate frequent low NCOA6 expression with frequent high EGFR expression in aggressive AA PCs and demonstrate that NCOA6 loss-caused EGFR OE plays a key role in promotion of AA CRPC development. In Specific Aim 2, we plan to dissect the molecular events responsible for NCOA6 loss-caused EGFR OE in AA PC cells. We found NCOA6 interacts with NFY transcription factor and associates with a distant putative EGFR enhancer. We will carry out a cluster of experiments involving enhancer mapping, protein-protein and protein- DNA interactions, chromatin looping, and enhancer-promoter interaction. These experiments will address how the NCOA6:NFY complex at the putative enhancer prevents EGFR OE and how NCOA6 loss causes EGFR OE. Collectively, successful outcomes of this project will establish a conceptual model, in which NCOA6 works with NFY to repress the distant EGFR enhancer, which prevents EGFR OE and AA CRPC development. Frequent NCOA6 downregulation causes frequent EGFR OE, which promotes PC and CRPC development and drives AA PC disparity. Accomplishment of this project will also help our next phase research to develop low NCOA6 and high EGFR as diagnostic/prognostic markers for selecting AA CRPC patients for personalized treatment.

项目概要/摘要 与欧洲裔美国（EA）男性相比，非洲裔美国（AA）男性的前列腺水平明显更高 癌症（PC）的发病率，并且他们的 PC 更有可能变得具有去势抵抗性、转移性和致命性。这是 目前还不清楚是什么原因导致了这种 AA PC 差异。过度表达的 EGFR 可致癌，且 EGFR 更易致癌 与 EA PC 相比，AA PC 中经常过度表达，但目前仍不清楚 EGFR 的原因 过度表达（OE）。我们发现 NCOA6，一种具有多效性功能的转录共调节因子，经常被 在 AA PC 中下调，其缺失导致 AA PC 细胞中出现 EGFR OE。我们还发现淘汰赛（KO） NCOA6 与杂合 Pten 一起促进前列腺上皮增生，形成快速生长、侵袭性、 小鼠前列腺中的转移性致命 PC。基于这些发现，我们假设 NCOA6 更 与 EA PC 相比，AA PC 中频繁下调，其频繁下调与 侵袭性 AA PC 中常见 EGFR OE，预后不良。我们还假设 NCOA6 丢失会导致 EGFR OE，进而促进去势抵抗性 PC (CRPC) 的发展。在具体目标 1 中，我们计划 将 NCOA6 低表达与 AA PC 中 EGFR OE 和 CRPC 的发展相关联。具体来说，我们将 测量并比较 AA 和 EA PC 中的 NCOA6 和 EGFR 蛋白表达水平并进行匹配 邻近的正常前列腺组织标本，并进行全面的数据分析。我们希望找到更高的 与 EA PC 相比，具有低 NCOA6 和高 EGFR 表达的 AA PC 的百分比，这将连接 NCOA6 的频繁下调导致 AA PC 差异的发展。我们还将检查是否 NCOA6 缺失可促进雄激素敏感的 AA PC 细胞发展为 CRPC，NCOA6 缺失是否会促进雄激素敏感的 AA PC 细胞发生 CRPC？ 促进的 CRPC 依赖 EGFR OE 生长和生存。如果成功的话，这些研究的结果将 将侵袭性 AA PC 中频繁的低 NCOA6 表达与频繁的高 EGFR 表达联系起来 证明NCOA6缺失导致的EGFR OE在促进AA CRPC发展中发挥关键作用。在 具体目标 2，我们计划剖析 AA PC 中 NCOA6 丢失导致 EGFR OE 的分子事件 细胞。我们发现 NCOA6 与 NFY 转录因子相互作用，并与遥远的假定 EGFR 相关联 增强剂。我们将进行一系列实验，涉及增强子作图、蛋白质-蛋白质和蛋白质- DNA 相互作用、染色质循环和增强子-启动子相互作用。这些实验将解决如何 假定增强子处的 NCOA6:NFY 复合物可预防 EGFR OE，以及 NCOA6 缺失如何导致 EGFR OE。 总的来说，该项目的成功成果将建立一个概念模型，其中 NCOA6 与 NFY 抑制远端 EGFR 增强子，从而阻止 EGFR OE 和 AA CRPC 的发展。经常 NCOA6 下调导致频繁的 EGFR OE，从而促进 PC 和 CRPC 的发展并驱动 AA 个人电脑的差距。该项目的完成也将有助于我们下一阶段研究开发低NCOA6和 高 EGFR 作为选择 AA CRPC 患者进行个性化治疗的诊断/预后标志物。