Regulation of androgen receptor function by H3K4 methylation in prostate cancer Project Summary The evolution of prostate cancer from an androgen-dependent state (ADPC) to one that is castration- resistant (CRPC) marks the lethal progression of the disease. Understanding the pathogenesis of CRPC and development of novel therapies for CRPC remains an urgent need. The androgen receptor (AR), a ligand-dependent transcription factor, is still expressed and functional in CRPC;however, how AR regulates target genes in CRPC and the functional roles of AR target genes in CRPC is poorly understood. In preliminary studies we have found that AR selectively binds to enhancer regions of M- phase cell cycle genes (e.g. UBE2C) in a CRPC cell model but not in an ADPC cell model, leading to higher M-phase gene expression and faster growth of CRPC than of ADPC. Interestingly, we further found that increased histone H3 lysine 4 (H3K4) methylation level on the M-phase gene enhancers is the underlying mechanism for selective AR binding at M-phase gene enhancers in CRPC compared with ADPC. However, these studies are limited to identifying and characterizing a few enhancer H3K4 methyaltion regulated AR target genes in a pair of CRPC/ADPC cell models. In this proposal we hypothesize that enhancer and promoter H3K4 methylation directs AR in the global regulation of target genes involved in critical processes such as growth and invasion in CRPC.
Our specific aims are to: (1) To determine whether the enhancer H3K4 methylation and AR play a causal role in regulating UBE2C expression and to investigate the functional role of UBE2C in various CRPC cell models and in tumorigenesis in vivo. The hypothesis that UBE2C is a direct enhancer H3K4 methylation and AR co- regulated gene that plays a critical role in growth and invasion of at least a subset of CRPC cell models and in tumorigenesis in vivo will be tested in this aim. (2) To globally identify and characterize enhancer/promoter H3K4 methylation and AR co-regulated genes in CRPC cells. The hypothesis that gain of H3K4me2 directs distal enhancer-bound AR to activate oncogenes, whereas loss of H3K4me2 and/or H3K4me3 leads to enhancer- and/or promoter-bound AR-mediated silencing of tumor suppressor genes in CRPC will be tested in this aim. (3) To examine the relevance of H3K4 methylation/AR regulation of target genes in human prostate cancer samples. The hypothesis that the data obtained from Aims 1 and 2 is relevant to human prostate cancer will be evaluated in CRPC and ADPC samples in this aim.

Public Health Relevance

Regulation of androgen receptor function by H3K4 methylation in prostate cancer Relevance Altered histone H3K4 methylation in castration-resistant prostate cancer may direct androgen receptor in the regulation of downstream target genes involved in critical processes such as growth and invasion. This proposal will significantly increase our understanding of the molecular and cellular outcomes of H3K4 methylation and AR co-regulation in prostate cancer, which has translational implications in the development of new therapies and identification of new biomarkers in prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151979-04
Application #
8700336
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Woodhouse, Elizabeth
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ye, Zhenqing; Chen, Zhong; Sunkel, Benjamin et al. (2016) Genome-wide analysis reveals positional-nucleosome-oriented binding pattern of pioneer factor FOXA1. Nucleic Acids Res 44:7540-54
Sunkel, Benjamin; Wu, Dayong; Chen, Zhong et al. (2016) Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence. Nucleic Acids Res 44:4105-22
Chen, Kaifu; Chen, Zhong; Wu, Dayong et al. (2015) Broad H3K4me3 is associated with increased transcription elongation and enhancer activity at tumor-suppressor genes. Nat Genet 47:1149-57
Chen, Zhong; Lan, Xun; Wu, Dayong et al. (2015) Ligand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer. Nat Commun 6:8323
Chen, Zhong; Lan, Xun; Thomas-Ahner, Jennifer M et al. (2015) Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer. EMBO J 34:502-16
He, Huiling; Li, Wei; Liyanarachchi, Sandya et al. (2015) Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. Proc Natl Acad Sci U S A 112:6128-33
Wu, Dayong; Sunkel, Benjamin; Chen, Zhong et al. (2014) Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res 42:3607-22
Ye, Zhenqing; Chen, Zhong; Lan, Xun et al. (2014) Computational analysis reveals a correlation of exon-skipping events with splicing, transcription and epigenetic factors. Nucleic Acids Res 42:2856-69
Zhang, Mei; Manchanda, Parmeet K; Wu, Dayong et al. (2014) Knockdown of PRKAR1A, the gene responsible for Carney complex, interferes with differentiation in osteoblastic cells. Mol Endocrinol 28:295-307
He, Huiling; Li, Wei; Wu, Dayong et al. (2013) Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance. PLoS One 8:e61920

Showing the most recent 10 out of 15 publications