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

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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.