NCOA6 REPRESSES PROSTATE CANCER THROUGH INHIBITING EGFR ENHANCER ACTIVITY TO PREVENT EGFR OVEREXPRESSION

Abstract

Advanced prostate cancer (PCa) is a malignant disease with high mortality. Meanwhile, a substantial proportion of PCa is indolent and rarely progresses to advanced stages. Patients with indolent PCa are often overtreated since biomarkers to distinguish advanced PCa from indolent diseases are largely undefined. Hence, there is an urgent need to identify therapeutic targets for treating advanced PCa and biomarkers for distinguishing advanced PCa from indolent diseases. Here, I found that prostate epithelial cell-specific KO of Ncoa6 causes prostatic intraepithelial neoplasia (PIN) in mice. Prostate epithelial cell-specific KO of Ncoa6 in a Pten heterozygous background causes lethal metastatic PCa in mice. Prostate epithelial cell-specific KO of Ncoa6 in a Pten homozygous KO background accelerates PCa progression and metastasis. Combined analysis of gene expression profiling and ChIPseq data revealed that EGFR is a direct target gene of NCOA6. Consistently, NCOA6 KO results in EGFR upregulation in both 22Rv1 human PCa cells and mouse prostate tumor cells. Mechanistically, NCOA6 is recruited by transcription factor NF-Y to a previously unknown EGFR enhancer where NCOA6 prevents acetylation at histone 3 lysine 27 (H3K27) through inhibiting p300 recruitment, causing a decrease in EGFR enhancer activity. Importantly, treatment with EGFR inhibitor Erlotinib caused remarkable shrink of Ncoa6 KO-induced PCa at both primary and metastatic sites in a Pten heterozygous background. Strikingly, NCOA6 protein is downregulated and EGFR protein is upregulated in a subset of human PCa samples compared to the paired normal prostate samples from both European American (EA) and African American (AA) patients. Approximately 11% of human primary PCa samples and 36% of human metastatic PCa samples concurrently express low NCOA6 and high EGFR, which is associated with higher risks to develop aggressive PCa. Besides, NCOA6 protein is downregulated and EGFR protein is upregulated in a subset of human metastatic PCa specimens compared to primary PCa specimens. In summary, I found that NCOA6 is a PCa suppressor in mouse PCa models and human PCa cells, uncovered the underlying mechanisms responsible for NCOA6 as a PCa suppressor, and demonstrated that NCOA6 is downregulated in a subset of human PCa. My findings suggest that NCOA6 is a promising biomarker to distinguish aggressive PCa from indolent prostate tumors, and that NCOA6 deficiency-activated EGFR signaling could be a therapeutic target for treating NCOA6 deficiency-promoted PCa.