Androgen receptor plays a significant role in prostate carcinogenesis and its overexpression and aberrant activation are considered to be the underlying cause for the development of castration- resistant tumors, which at present defy any effective treatment. As a transcriptional factor, androgen receptor is involved in the assembly of transcriptional complex including coactivators on the target genome site. One special class of coactivators are histone modifying enzymes and the best understood are histone acetylases. A newly emerging class is histone demethylase, which serves to remodel the chromatin surrounding the androgen receptor binding site. They are thus both transcriptional coactivator and epigenetic regulator. The present proposal is based on our identification of a new histone demethylase with all the hallmarks of a strong coactivator of androgen receptor and is overexpressed in prostate cancer. It enhances androgen response, accelerates cell cycle progression, and exhibits a substrate specificity different from the known histone demethylases. Intriguingly, it is regulated by growth factor and is phosphorylated by tyrosine kinases. The enzyme is cell cycle regulated but also regulates cell cycle. Based on these preliminary observations, we wish to elucidate its biochemical properties as a demetylation enzyme, its regulation as a signal transducer, and its biological effects as an androgen receptor coactivator. Its potential as a biomarker and/or a target for therapy will also be evaluated.

Public Health Relevance

Health Relevance Increasing evidence suggests that over 90% of castration-resistant prostate cancers have evolved ways to aberrantly activate androgen receptor either due to androgen receptor mutations, amplification, increase of intracrine androgen, posttranslational modification of androgen receptor or association of deregulated coactivators. Thus, targeting aberrantly activated androgen receptor or its dysregulated coactivators is likely to be the most fruitful strategy to interfere with the development of hormone-refractory tumors. Strategy to interfere with ligand binding is one option, but it fails to target truncated androgen receptor. Targeting co-activators is another strategy, but most of the co-activators are not enzymes, which makes the development of small-molecule inhibitors more difficult. Our finding that histone demethylase, an enzyme, is a coactivator thus offers an ideal target for this intervention. If SAHA, an inhibitor for histone deacetylase and a clinically approved drug, is a pertinent example, this new histone demethylase could be an ideal enzyme-based target for prostate cancer. Their consistent overexpression in prostate cancer specimens shown in our preliminary data suggests it could also potentially be a good biomarker for aberrant activation of androgen receptor. The overall relevance of this proposal to prostate cancer includes : 1) It offers a new handle to understand the epigenetic regulation of androgen receptor activity and thus prostate cancer development. 2) It offers a potentially new biomarker for transformation and/or aberrant activation of androgen receptor in the prostate carcinogenesis, and 3) It offers a potentially new enzyme- based target for interfering with prostate carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA150197-03
Application #
8217304
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Mohla, Suresh
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$309,544
Indirect Cost
$108,269
Name
University of California Davis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Kuo, Ching-Ying; Cheng, Chun-Ting; Hou, Peifeng et al. (2016) HIF-1-alpha links mitochondrial perturbation to the dynamic acquisition of breast cancer tumorigenicity. Oncotarget 7:34052-69
Wang, Junjian; Zou, June X; Xue, Xiaoqian et al. (2016) ROR-? drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med 22:488-96
Cheng, Chun-Ting; Kuo, Ching-Ying; Ouyang, Ching et al. (2016) Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells. Cancer Res 76:5006-18
Kao, C-J; Martiniez, A; Shi, X-B et al. (2014) miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT. Oncogene 33:2495-503
Changou, Chun A; Chen, Yun-Ru; Xing, Li et al. (2014) Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy. Proc Natl Acad Sci U S A 111:14147-52
Guo, W; Liu, R; Bhardwaj, G et al. (2014) Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. Cell Death Dis 5:e1409
Guo, Wenchang; Liu, Ruiwu; Bhardwaj, Gaurav et al. (2013) CTA095, a novel Etk and Src dual inhibitor, induces apoptosis in prostate cancer cells and overcomes resistance to Src inhibitors. PLoS One 8:e70910
Changou, Chun A; Wolfson, Deanna L; Ahluwalia, Balpreet Singh et al. (2013) Quantitative analysis of autophagy using advanced 3D fluorescence microscopy. J Vis Exp :e50047
Tsai, Hui-Chi; Boucher, David L; Martinez, Anthony et al. (2012) Modeling truncated AR expression in a natural androgen responsive environment and identification of RHOB as a direct transcriptional target. PLoS One 7:e49887
Wang, L-Y; Kung, H-J (2012) Male germ cell-associated kinase is overexpressed in prostate cancer cells and causes mitotic defects via deregulation of APC/CCDH1. Oncogene 31:2907-18

Showing the most recent 10 out of 14 publications