- Project 4 A prominent feature of castration resistant prostate cancer (CRPC) is an altered lipid environment. Oncogenic changes in androgen receptor- (AR)-dependent transcription dramatically upregulate lipid, sterol, and cholesterol metabolism. Hypercholesterolemia promotes prostate tumor growth, upregulates the steroidogenic enzyme CYP17, increases intratumoral but not circulating androgen, and activates oncogenic signaling pathways. Aggressive PC cells sequester cholesterol by a variety of mechanisms, including upregulation of lipid synthesis, enhanced lipoprotein uptake and down-regulation of sterol export. Epidemiological evidence has linked use of cholesterol-lowering drugs, particularly HMG-CoA reductase inhibitors (statins), with reduced risk of CRPC. In collaboration with Project 1: Chung, we demonstrated for the first time that high circulating cholesterol, with energy intake held constant, promotes metastasis to bone in cooperation with activated RANK. Recently, our lab was the first to report that the chromatin protein, scaffold attachment factor B1 (SAFB1), can act as an AR co-repressor at androgen-responsive genes. SAFB1 is genomically inactivated at high frequency in CRPC and exhibits other characteristics of a tumor suppressor. SAFB1 forms a complex with the histone methyltransferase EZH2, a PC oncoprotein, and with the AR to regulate gene expression by a mechanism involving histone modification. SAFB1 knockdown in PC cells perturbs a transcriptional network of ~900 genes and results in an aggressive phenotype, including resistance to androgen withdrawal. Analysis of this SAFB1-loss network indicates broad effects on sterol/lipid metabolism and chromatin modification. Most of these perturbed genes appear to be distinct from AR- and EZH2-dependent pathways and thus may be largely unstudied in PC. The SAFB1-loss network also converges on androgen metabolism genes in the RANK-mediated network under study in Project 1. There is currently little understanding of how epigenomic alterations seen in PC contribute to the enhanced cholesterol and steroidogenic tumor cell phenotype that emerges in late-stage disease, or how this phenotype might be therapeutically targeted. Based on these novel findings, we will test the hypothesis that SAFB1 loss activates a novel transcriptional program that alters lipid metabolism in a manner that elevates intratumoral cholesterol and androgenic sterols, and enhances intracrine pathways of AR activation. The physiologic significance of SAFB1 loss will be tested within the P01 using 3D culture systems (with Project 2: Farach-Carson), xenografts (with Project 1) and a large series of treatment nave metastatic cases (Project 3:Bhowmick).
The specific aims are:
Aim 1. Test the hypothesis that the chromatin scaffold SAFB1 regulates AR/EZH2- dependent and AR/EZH2-independent transcriptional programs that drive PC metastasis.
Aim 2. Test the hypothesis that SAFB1 loss alters lipid metabolism, intracrine androgen signaling and cooperates with RANKL- dependent mechanisms to promote PC metastasis.

Public Health Relevance

- Project 4 This project centers on determining the role of a DNA-binding protein, SAFB1, in prostate cancer. Loss of SAFB1 function, which occurs in castration-resistant prostate cancer, may promote disease progression and resistance to hormone therapy. We will test the hypothesis that SAFB1 loss appears to be a critical event in progression to advanced disease and that SAFB1 silencing represents a novel therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA098912-14
Application #
9439717
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Stewart, Paul A; Khamis, Zahraa I; Zhau, Haiyen E et al. (2017) Upregulation of minichromosome maintenance complex component 3 during epithelial-to-mesenchymal transition in human prostate cancer. Oncotarget 8:39209-39217
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Tighiouart, Mourad; Cook-Wiens, Galen; Rogatko, André (2017) A Bayesian adaptive design for cancer phase I trials using a flexible range of doses. J Biopharm Stat :1-13
Tighiouart, Mourad; Li, Quanlin; Rogatko, André (2017) A Bayesian adaptive design for estimating the maximum tolerated dose curve using drug combinations in cancer phase I clinical trials. Stat Med 36:280-290

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