Unraveling the Regulatory Role of the CYP27A1-27HC-KLF4 Axis in Prostate Cancer
Abstract
Rationale: Prostate cancer (PC) is the most common cancer in men after skin cancers. Clinical and scientific studies have shown that PC cells accumulate high levels of cellular cholesterol, suggesting that the mechanism to balance normal levels of cellular cholesterol is deregulated. Our laboratory recently published a study describing that CYP27A1, an enzyme that normally converts cholesterol to 27-hydroxycholesterol (27HC) in the first step of cholesterol breakdown and excretion, is commonly lost in PC. When we restored CYP27A1 expression in PC cells that have lost CYP27A1, we observed increased 27HC levels, reduced cell growth, and decreased intracellular cholesterol. Likewise, direct treatment of PC cells with 27HC reduced proliferation and cellular cholesterol. Moreover, 27HC treatment also reduced PC tumor growth in mice that were fed a high cholesterol diet. Together, these studies show that PC tumors deregulate cholesterol homeostasis by reducing expression of CYP27A1 and, consequently, 27HC. Thus, 27HC may have clinical utility as a novel PC therapy. We performed preliminary studies that have identified transcription factors that potentially mediate 27HC treatment (27HC-TFs), with our focus on one 27HC-TF named Krueppel-like factor 4 (KLF4). Defining the cellular pathways regulated by 27HC-mediated KLF4 action in PC cells will allow us to better understand how altering cellular cholesterol causes PC and will ultimately enable us to create better drugs to target these pathways in PC. Additionally, we also found that 27HC reduces levels of an enzyme, squalene epoxidase (SQLE), which is important for the synthesis of cellular cholesterol. A population study recently showed that men with PC who had high levels of SQLE in their prostate tissue were more likely to die of PC. That said, there are no basic science/functional studies to date to understand the role of SQLE in PC. Taken together, the goal of this proposal is to further understand how 27HC mediates its anti-PC function via a 27HC-TF (KLF4) and whether high levels of SQLE lead to more aggressive PCs by increasing cholesterol production in the cell. Applicability: Data from our laboratory indicate that PC tumors accumulate high cholesterol compared to the normal prostate tissue, in part by downregulating CYP27A1, which converts cholesterol to 27HC, an intracellular cholesterol biosensor. The goal of this project is to understand how a specific 27HC-TF regulates the anti-PC mechanism of action of 27HC by use of bioinformatics tools (Aim 1) and to understand the role of SQLE in PC (Aim 2). Although this proposal focuses on a discovery science aspect of PC, the knowledge we gain about the pathways regulated by anti-PC agent, 27HC, will help in narrowing down potential targets for drug development in men with PC. Career Goals: My long-term goal is to reduce the burden and morbidity of PC by performing innovative and cutting-edge research, with the goal of discovering effective and novel PC therapies. To accomplish this, I would like to receive training in bioinformatics and large data analysis to become a bridge between bioinformaticians and clinicians in order to execute clinically relevant studies. To develop these skills, I will be supported by a mentoring team of three prominent PC scientists at Cedars-Sinai: (1) Dr. Stephen Freedland (primary mentor; Professor of Surgery and Director of the Center for Integrated Research on Cancer and Lifestyle), a physician-scientist and world leader in studies of cholesterol-lowering and PC risk; (2) Dr. Michael Freeman (co-mentor; Vice-Chair and Director of Research, Department of Surgery), a basic scientist expert on cholesterol in PC; and (3) Dr. Sungyong You (co-mentor; Assistant Professor of Surgery), who is the Genitourinary Bioinformatic group leader, with a strong background in computational biology and analysis of large-scale genomic and transcriptomic data. Under this team, I will gain expo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810575
Entities
People
- Shweta Dambal
Organizations
- Cedars-Sinai Medical Center
- United States Army