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

项目摘要/摘要 与欧洲裔美国人(EA)男性相比，非裔美国人(AA)男性的前列腺明显更高 癌症(PC)的发病率，以及他们的PC更有可能变得耐阉割，转移和致命。它是 仍然不清楚是什么导致了这种AA PC差异。过度表达的EGFR可能是致癌的，而且EGFR的 与EA PC相比，AA PC中经常过度表达，但仍不清楚是什么导致了EGFR 过度表达(OE)。我们发现，NCOA6，一种具有多效性功能的转录辅助调节因子，经常 在AA PC中下调，它的缺失导致AA PC细胞中的EGFR OE。我们还发现基因敲除(KO) NCOA6促进Pten杂合子前列腺上皮增生快速生长，侵袭性， 小鼠前列腺中的转移性致死PC。基于这些发现，我们假设NCOA6比 在AA PC与EA PC中频繁下调，其频繁下调与 侵袭性AA PC常发生EGFR OE，预后差。我们还假设NCOA6的损失会导致 EGFR OE，进而促进抗去势PC(CRPC)的发展。在具体目标1中，我们计划 AAPC中低表达的NCOA6与EGFR OE和CRPC的发生有关。具体来说，我们将 测量和比较AA和EA PC及其配对的NCOA6和EGFR蛋白表达水平 取邻近正常前列腺组织标本，进行全面的数据分析。我们希望找到更高的 与将连接的EA PC相比，低NCOA6和高EGFR表达的AA PC的百分比 NCOA6的频繁下调给AA PC的发展带来了悬殊。我们还将研究是否 NCOA6缺失可促进雄激素敏感型AA PC细胞发生CRPC，而NCOA6缺失是否可促进雄激素敏感的AA PC细胞发生CRPC 促进的CRPC依赖于EGFR OE生长和生存。如果成功，这些研究的结果将 侵袭性再障PC中NCOA6的频繁低表达与EGFR的频繁高表达 证明NCOA6亏损导致的EGFR OE在促进AA CRPC发展中起着关键作用。在……里面 具体目标2，我们计划剖析导致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，并与远距离推测的EGFR有关 增强剂。我们将进行一系列实验，涉及增强子图谱、蛋白质-蛋白质和蛋白质- DNA相互作用、染色质环和增强子-启动子相互作用。这些实验将解决如何 推测的增强子上的NCOA6：NFY复合体可以阻止EGFR OE，以及NCOA6的缺失如何导致EGFR OE。 总的来说，该项目的成功成果将建立一个概念模型，在该模型中，NCOA6将与 NFY抑制遥远的EGFR增强子，阻止EGFR OE和AA CRPC的发展。频密 NCOA6下调导致频繁的EGFR OE，这促进了PC和CRPC的发展，并推动了AA PC差异。该项目的完成也将有助于我们下一阶段的研究开发低NCOA6和 高EGFR可作为选择AA CRPC患者个体化治疗的诊断/预后指标。

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.