Characterizing the Prostate Cancer-Suppressive Role of NCOA6 and Targeting Its Deficiency-Activated Pathway for Treating Prostate Cancer
Abstract
Prostate cancer (PCa) is the most common cancer in American men. Prostate tumors are heterogeneous, ranging from slow-growing and non-metastatic indolent tumors to fast-growing, metastatic, and lethal PCas. The lack of sufficient knowledge, biomarkers, and therapeutic targets for PCa progression, diagnosis, prognosis, and treatment present two major problems. The first is that patients with indolent prostate tumors cannot be steadily distinguished from patients with aggressive PCas; therefore, they may be unnecessarily overtreated with anti-cancer drugs with adverse effects. The second is that most patients with aggressive metastatic PCas remain incurable. This study will address some aspects of these two overarching challenges by understanding why and how the loss of NCOA6 expression strongly promotes indolent prostate tumors’ progression into fast-growing, metastatic, and lethal PCas and whether targeting the NCOA6 loss-activated cancer drivers can inhibit aggressive PCa cell growth and metastasis. Ncoa6 is a large protein expressed in the prostate and is involved in gene regulation. From examining a small number of prostate normal and cancerous tissue specimens from European and African American men, we found that NCOA6 is significantly decreased in cancerous tissues. I decided to take a human to mouse model to human experimental approach to study the role of NCOA6 in PCa. Using genetically engineered mouse models of human cancer, I found that inactivation of NCOA6 drastically accelerates prostate carcinogenesis, driving indolent prostate tumors to progress into fast-growing, metastatic, and lethal PCas. Furthermore, I also found that ablation of NCOA6 in human PCa cells caused overexpression of the epithelial growth factor receptor (EGFR). EGFR overexpression is known to drive cancer growth and metastasis. Based on these findings, I hypothesize that NCOA6 is a powerful PCa suppressor downregulated in human PCas. NCOA6 represses PCas by repressing EGFR expression. PCas with low levels of NCOA6 should have high levels of EGFR, and patients with this subgroup of cancers should have a poor prognosis and shorter survival time. Targeting EGFR should be effective to inhibit the growth and metastasis of these subgroup PCas. I propose two specific aims to test my hypothesis. Aim 1 is to understand the mechanisms for NCOA6 loss-induced EGFR overexpression in PCa and to target the overexpressed EGFR for inhibiting the growth of PCa with NCOA6 downregulation and EGFR overexpression. In pursuing this aim, I will study the complex molecular mechanisms regarding how NCOA6 interacts with and represses the function of the gene regulation protein complex consisting of NFYa/b/c and p300. I plan to demonstrate that NFYa/a/c and NCOA6 are associated with the EGFR gene to control EGFR expression at a low or normal level. NCOA6 downregulation in cancer cells permits NFYa/b/c to interact with p300 to increase EGFR expression, which in turn makes cancer cells grow faster and more aggressively. I will also test whether inhibition of EGFR with drugs can stop the growth and metastasis of PCa cells expressing low NCOA6 and high EGFR. EGFR inhibitors are currently used in clinical trials for treating some other cancers. Once its effectiveness is proven for PCa, clinical trials for treating PCa with EGFR inhibitors can be followed shortly. Aim 2 is to examine the expression patterns of NCOA6 and EGFR proteins and to determine the clinical significance of NCOA6 downregulation and EGFR overexpression in human prostate tumors. I predict that low NCOA6 is associated with high EGFR in a subset of aggressive human PCas with poor prognosis, which will validate our findings from studying cell lines, mouse models, and a small human PCa cohort. My career goal is to become an independent faculty member doing PCa research and training students and postdocs in a university with a good research environment. By doing the proposed PCa s
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910386
Entities
People
- Yonghong Liu
Organizations
- Baylor College of Medicine
- United States Army