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: 10544740
• 负责人: JIANMING XU
• 金额: $ 18.33万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544740
• 关键词: Acceleration; Address; African American; American; Androgens; Binding; Biological Assay; Cancer Cell Growth; Cancer Patient; Castration; Cell model; Chromatin; Chromatin Conformation Capture and Sequencing; Chromatin Loop; Collaborations; Combined Modality Therapy; Complex; Coupled; DNA-Protein Interaction; Data Analyses; Development; Diagnostic; Diet; Distant; Down-Regulation; EGFR Protein Overexpression; Enhancers; Epidermal Growth Factor Receptor; Epithelium; Ethnic Origin; European; Event; Future; Genetic; Genetic Transcription; Growth; Heterozygote; Hyperplasia; Immune response; Incidence; Knock-out; Knowledge; Letters; Loss of Heterozygosity; Malignant neoplasm of prostate; Maps; Measures; Mediating; Metabolic; Modeling; Molecular; Mus; Mutate; Mutation; Nuclear Receptors; Oncogenic; Outcome; Outcome Study; Pathway interactions; Performance; Phase; Play; Prognosis; Prognostic Marker; Prostate; Prostatic; Proteins; Proto-Oncogenes; Receptor Up-Regulation; 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; 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; programs; 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.

项目摘要/摘要 与欧美（EA）男性相比，非裔美国人（AA）男性的前列腺明显更高 癌症（PC）发病率及其PC更有可能变得耐法，转移性和致命性。这是 仍然不清楚是什么原因导致AA PC差异。过表达的EGFR可能是致癌的，EGFR更具 与EA PC相比，AA PC中经常过表达 过表达（OE）。我们发现NCOA6是一种具有多效函数的转录核心调节器，经常是 在AA PC中下调，其损耗导致AA PC细胞中的EGFR OE。我们还发现 NCOA6用杂合PTEN促进前列腺上皮增生，以发展快速增长，侵入性， 小鼠前列腺中的转移性PC。根据这些发现，我们假设NCOA6更多 经常在AA PC与EA PC中下调，其频繁下调与 在预后不良的侵略性AA PC中，经常出现EGFR OE。我们还假设NCOA6损失原因 EGFR OE又促进了耐castration-PC（CRPC）的开发。在特定目标1中，我们计划 将低NCOA6表达与AA PC中的EGFR OE和CRPC开发相关联。具体来说，我们会的 测量和比较AA和EA PC中的NCOA6和EGFR蛋白表达水平并匹配 相邻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 频繁的NCOA6下调用于AA PC差异的发展。我们还将检查是否 NCOA6丢失可以促进对雄激素敏感的AA PC细胞发展CRPC，以及NCOA6损失是否损失 - 促进的CRPC依靠EGFR OE生长和生存。如果成功，这些研究的结果将 在侵略性AA PC中，频繁的低NCOA6表达与EGFR频繁的高度表达和 证明nCOA6引起的EGFR OE在促进AA CRPC开发中起着关键作用。在 具体目标2，我们计划剖析AA PC中负责NCOA6损失引起的EGFR OE的分子事件 细胞。我们发现NCOA6与NFY转录因子相互作用，并与遥远的推定EGFR相互作用 增强剂。我们将进行一系列实验，涉及增强剂映射，蛋白质 - 蛋白质和蛋白质 - DNA相互作用，染色质循环和增强子促销相互作用。这些实验将解决如何 推定增强剂处的NCOA6：NFY复合物可阻止EGFR OE以及NCOA6损耗如何导致EGFR OE。 总的来说，该项目的成功结果将建立一个概念模型，其中NCOA6与之合作 NFY抑制遥远的EGFR增强子，从而防止EGFR OE和AA CRPC开发。频繁 NCOA6下调导致EGFR OE频繁，从而促进PC和CRPC开发并驱动AA PC差异。该项目的完成还将帮助我们下一阶段的研究发展低NCOA6和 高EGFR作为诊断/预后标记，用于选择AA CRPC患者进行个性化治疗。