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.

项目总结/摘要 与欧洲裔美国人（EA）男性相比，非洲裔美国人（AA）男性的前列腺 癌症（PC）的发病率，他们的PC更有可能成为去势抵抗，转移和致命。是 目前还不清楚是什么原因导致了AA PC的差异。EGFR过表达可致癌，EGFR表达越高， 与EA PC相比，在AA PC中经常过表达，但仍不清楚是什么导致EGFR 过表达（OE）。我们发现NCOA 6是一种具有多效性功能的转录辅助调节因子， 在AA PC中下调，其缺失导致AA PC细胞中的EGFR OE。我们还发现，敲除（KO） NCOA 6促进具有杂合子Pten的前列腺上皮增生发展为快速生长的、侵袭性的， 小鼠前列腺中的转移性致命PC。基于这些发现，我们假设NCOA 6比NCOA 6更重要。 与EA PC相比，AA PC中频繁下调，并且其频繁下调与 侵袭性AA PC中EGFR OE频繁，预后不良。我们还假设NCOA 6损失导致 EGFR OE，反过来促进去势抵抗性PC（CRPC）的发展。在具体目标1中，我们计划 在AA PC中，低NCOA 6表达与EGFR OE和CRPC发展相关。具体来说，我们将 测量并比较AA和EA PC中的NCOA 6和EGFR蛋白表达水平， 相邻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NCOA 6和高EGFR表达的AA PC的百分比，其将连接 NCOA 6的频繁下调与AA PC差异的发展有关。我们还将研究是否 NCOA 6缺失可以促进雄激素敏感的AA PC细胞发育CRPC，并且NCOA 6缺失- 促进CRPC依赖于EGFR OE生长和存活。如果成功，这些研究的结果将 在侵袭性AA PC中，将频繁的低NCOA 6表达与频繁的高EGFR表达相关联， 证明NCOA 6缺失引起的EGFR OE在促进AA CRPC发展中起关键作用。在 具体目标2，我们计划剖析导致AA PC中NCOA 6丢失导致EGFR OE的分子事件 细胞我们发现NCOA 6与NFY转录因子相互作用，并与一个远距离的假定EGFR相关 增强剂我们将进行一系列实验，包括增强子定位、蛋白质-蛋白质和蛋白质- DNA相互作用、染色质成环和增强子-启动子相互作用。这些实验将解决如何 假定增强子上的NCOA 6：NFY复合物阻止EGFR OE以及NCOA 6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NCOA 6与 NFY抑制远端EGFR增强子，从而阻止EGFR OE和AA CRPC的发展。频繁 NCOA 6下调导致频繁的EGFR OE，其促进PC和CRPC的发展并驱动AA PC差异。该项目的完成也将有助于我们下一阶段的研究，以开发低NCOA 6， 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。