Education & Training
- University of Science & Technology of China B.S. 07/1983 Molecular Biology
- University of Pittsburgh Ph.D. 05/1990 Molecular Biology
- Carnegie Institution of Washington, Baltimore, MD Postdoc 12/1994 Molecular Endocrinology
A. Personal Statement
My lab studies the mechanisms of androgen action in the prostate and the mechanisms of two androgen dependent diseases, prostate cancer and benign prostatic hyperplasia (BPH). My long-term goal is to identify novel targets for developing new approaches to treat and/or prevent prostate cancer and BPH. My lab has discovered a potential nuclear export signal (NESAR) in androgen receptor (AR), providing new insights into the mechanism of AR nucleocytoplasmic trafficking. We have also developed a high-throughput screening and identified two closely related pyrroloimidazole-based small molecules, CPPI and EPPI, that can inhibit AR nuclear localization in CRPC cells as well as DHT-induced GFP-LBD (ligand-binding domain) nuclear localization and could significantly inhibit xenograft tumor growth. We have identified and characterized EAF2/U19, a tumor suppressor regulated by androgens and frequently down-regulated in prostate cancer. In our preclinical/translational studies, we showed that the survival of animals bearing androgen-sensitive prostate tumors on intermittent androgen deprivation therapy (IADT) can be significantly prolonged by using short off-cycles coupled with 5α-reductase inhibition. In an effort to explore the molecular mechanisms leading to benign prostatic hyperplasia (BPH), our recent studies provided evidence for an increased permeability in BPH luminal epithelial cellular junctions. Also, we discovered a 4-fold increase in androgen-responsive gene expression in BPH epithelial cells as compared to the normal adjacent epithelial cells in clinical specimens. I have served as the Director of Urological Research since 2006, a Co-Leader of the Prostate Cancer Program at University of Pittsburgh Cancer Institute (UPCI) from 2006 to 2013, a Co-Leader of the Molecular and Cellular Cancer Biology Program at UPCI from 2014 to 2018, and Director of University of Pittsburgh O’Brien Urology Research Center since 2016. Publications relevant to this application include following:
a. O'Malley K.J., Dhir, R., Nelson, J.B., Bost, J., Lin, Y., and Wang, Z. The Expression of AndrogenResponsive Genes Is Up-Regulated in the Epithelia of Benign Prostatic Hyperplasia. The Prostate, 69: (16) 1716-23, 2009. PMCID: PMC2804845
b. O'Malley KJ, Eisermann K, Pascal LE, Parwani AV, Majima T, Graham L, Hrebinko K, Acquafondata M, Stewart NA, Nelson JB, Yoshimura N, Wang Z. Proteomic analysis of patient tissue reveals PSA protein in the stroma of benign prostatic hyperplasia. Prostate 2014 Jun;74(8):892-900. doi: 10.1002/pros.22807. Epub 2014 Apr 7. PMID:24711254 [PubMed - indexed for MEDLINE]
c. Li F, Pascal LE, Stolz DB, Wang K, Zhou Y, Chen W, Xu Y, Chen Y, Dhir R, Parwani AV, Nelson JB, DeFranco DB, Yoshimura N, Balasubramani GK, Gingrich JR, Maranchie JK, Jacobs BL, Davies BJ, Hrebinko RL, Bigley JD, McBride D, Guo P, He D, Wang Z. E-cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer. Prostate. 2019 Aug;79(11):1226-1237. doi: 10.1002/pros.23806. Epub 2019 Jun 18. PMID: 31212363.
d. Wang K, Pascal LE, Li F, Chen W, Dhir R, Balasubramani GK, DeFranco DB, Yoshimura N, He D, Wang Z. Tight junction protein claudin-1 is downregulated by TGF-β1 via MEK signaling in benign prostatic epithelial cells. Prostate. 2020 Jul 21. doi: 10.1002/pros.24046. Online ahead of print. PMID: 32692865
B. Positions and Honors
Positions and Employment
1984 - 1990 Graduate Research and Teaching Assistant, University of Pittsburgh, Pittsburgh, PA
1990 - 1994 Post-doctoral Fellow, Department of Embryology, Carnegie Institution of Washington, Baltimore, MD
1995 - 2002 Assistant Professor of Urology and Molecular Pharmacology, Northwestern University, Chicago, IL
1995 - 2006 Member, Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL
2002 - 2006 Associate Professor of Urology and Molecular Pharmacology, Northwestern University, Chicago, IL
2006 - present Director of Urological Research, Co-Director of Molecular and Cellular Cancer Biology Program, Professor of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Other Experience and Professional Memberships
1995 - present Active member, American Association for Cancer Research
1995 - present Member, The Endocrine Society
1996 - present Member, Society for Basic Urologic Research, Treasurer (2003 - 07), President (2011-12) 1998 - 2012 Member, DOD prostate cancer review panel
2002 - 2011 NIH study sections REN, UKGD, CAMP, and TCB, and UGPP (Chair 2013-2015)
2002 - 2009 Member, ACS TBE study section
2009 - present Editorial Board Member, The Prostate
2013 - 2019 Editorial Board Member, Endocrinology
2013 - present Ad hoc member, DOD prostate cancer programmatic review panel
1983 CUSBEA Finalist.
1996 - 1999 Recipient of a Junior Faculty Research Award from the American Cancer Society.
1996 - 1998 Recipient of an Edwin Beer Award from the New York Academy of Medicine.
1996 - 1997 Recipient of a CaPCURE Award.
1998 SBUR/Merck Young Investigator Award
2003 - 2006 O’Connor Family Research Professor of Urology
2006 NIH/NIDDK MERIT Award
2009 - present UPMC Chair in Urological Research
C. Contribution to Science
My lab has identified and characterized EAF2/U19, a tumor suppressor regulated by androgens and frequently down-regulated in prostate cancer.
1. Wang, Z., Tufts, R., Haleem, R., and Cai, X. Genes regulated by androgen in the rat ventral prostate. Proc Natl Acad Sci U S A, 94: 12999-13004, 1997. PMCID: PMC24252
2. Xiao, W., Zhang, Q., Jiang, F., Pins, M., Kozlowski, J. M., and Wang, Z. Suppression of prostate tumor growth by U19, a novel testosterone-regulated apoptosis inducer. Cancer Res, 63: 4698-4704, 2003.
3. Xiao, W., Zhang, Q., Habermacher, G., Yang, X., Zhang, A. Y., Cai, X., Hahn, J., Liu, J., Pins, M., Doglio, L., Dhir, R., Gingrich, J., and Wang, Z. U19/Eaf2 knockout causes lung adenocarcinoma, B-cell lymphoma, hepatocellular carcinoma and prostatic intraepithelial neoplasia. Oncogene, 27: 1536-1544, 2008. PMCID: PMC2800355
4. Ai J, Pascal LE, O'Malley KJ, Dar JA, Isharwal S, Qiao Z, Ren B, Rigatti LH, Dhir R, Xiao W, Nelson JB, Wang Z. Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model. Oncogene, 33: 2286-2294, 2014. PMCID: PMC3796117
To elucidate the mechanism of androgen receptor (AR) nucleocytoplasmic trafficking, we have identified and characterized a novel nuclear export signal (NESAR) in the ligand-binding domain (LBD) of AR. We have also found that the N-terminus domain (NTD) of AR can modulate AR subcellular localization. These findings will facilitate further studies to define the mechanisms of AR intracellular trafficking.
5. Saporita, A. J., Zhang, Q., Navai, N., Dincer, Z., Hahn, J., Cai, X., and Wang, Z. Identification and characterization of a ligand-regulated nuclear export signal in androgen receptor. J Biol Chem, 278: 41998-42005, 2003. PMID: 12923188.
6. Gong Y, Wang D, Dar JA, Singh P, Graham L, Liu W, Ai J, Xin Z, Guo Y, Wang Z. Nuclear Export Signal of Androgen Receptor (NESAR) Regulation of Androgen Receptor Level in Human Prostate Cell Lines via Ubiquitination and Proteasome-Dependent Degradation. 2012, Endocrinology 2012;153:5716-25. PMCID: PMC3512072.
7. Johnston, P. A., Nguyen, M. M., Dar, J. A., Ai, J., Wang, Y., Masoodi, K. Z., Shun, T., Shinde, S., Camarco, D. P., Hua, Y., Huryn, D. M., Wilson, G. M., Lazo, J. S., Nelson, J. B., Wipf, P., and Wang, Z. (2016) Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells. Assay and drug development technologies 14, 226-239. PMID: 27187604.
8. Masoodi, K. Z., Xu, Y., Dar, J. A., Eisermann, K., Pascal, L. E., Parrinello, E., Ai, J., Johnston, P. A., Nelson, J. B., Wipf, P., and Wang, Z. (2017) Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules. Molecular cancer therapeutics 16, 2120-2129. PMID: 28655783.
In our preclinical/translational studies, we showed that the survival of animals bearing androgensensitive prostate tumors on intermittent androgen deprivation therapy (IADT) can be significantly prolonged by using short off-cycle coupled with 5α-reductase inhibition. This finding provides the basis for developing potential clinical trials testing if the survival of prostate cancer patients on IADT can also be prolonged by short off-cycle coupled with 5α-reductase inhibition.
9. Eggener, S. E., Stern, J. A., Jain, P. M., Oram, S., Ai, J., Cai, X., Roehl, K. A., and Wang, Z. Enhancement of intermittent androgen ablation by "off-cycle" maintenance with finasteride in LNCaP prostate cancer xenograft model. Prostate, 66: 495-502, 2006. PMID: 16372330.
10. Wang, Y., Gupta, S., Hua, V., Ramos-Garcia, R., Shevrin, D., Jovanovic, B.D., Nelson, J.B., and Wang, Z. Prolongation of Off-Cycle Interval by Finasteride Is Not Associated with Survival Improvement in Intermittent Androgen Deprivation Therapy in LNCaP Tumor Model. Prostate, 70:(2):147-54, 2010, PMCID: PMC2805824.
11. Masoodi KZ, Ramos Garcia R, Pascal LE, Wang Y, Ma HM, O'Malley K, Eisermann K, Shevrin DH, Nguyen HM, Vessella RL, Nelson JB, Parikh RA, Wang Z. 5α-reductase inhibition suppresses testosterone-induced initial regrowth of regressed xenograft prostate tumors in animal models. Endocrinology. 2013 Jul;154(7):2296-307. PMID:23671262.
12. Laura E. Pascal and Khalid Z. Masoodi, Katherine J. O’Malley, Daniel Shevrin, Jeffrey R. Gingrich, Rahul A Parikh, Zhou Wang. 5α-reductase inhibition coupled with short off cycles increases survival in the LNCaP xenograft prostate tumor model on intermittent androgen deprivation therapy. J Urol. 2015 Apr;193(4):1388-93.PMID: 25444984Using PSA-CreERT2-based genetic lineage tracing in the mouse model, my lab has provided evidence that luminal epithelial cells in the adult prostate can survive androgen deprivation and are capable of proliferating upon androgen replacement. This suggests that regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate, which is fundamentally important for defining the cellular mechanism of androgen action in the adult prostate.
13. Liu J, Pascal LE, Isharwal S, Metzger D, Ramos Garcia R, Pilch J, Kasper S, Williams K, Basse PH, Nelson JB, Chambon P, Wang Z. Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Mol Endocrinol. 2011 Nov;25(11):1849-57. doi: 10.1210/me.2011-1081. Epub 2011 Sep 22. PMID: 21940754 [PubMed - indexed for MEDLINE] PMCID: PMC3198961
My lab was the first to use genetic lineage tracing in the mouse model to show that luminal epithelial cells in the adult prostate can survive androgen deprivation and are capable of proliferating upon androgen replacement. This suggests that regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate, which is fundamentally important for defining the cellular mechanism of androgen action in the adult prostate.
14. Liu J, Pascal LE, Isharwal S, Metzger D, Ramos Garcia R, Pilch J, Kasper S, Williams K, Basse PH, Nelson JB, Chambon P, Wang Z. Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Mol Endocrinol. 2011 Nov;25(11):1849-57. doi: 10.1210/me.2011-1081. Epub 2011 Sep 22. PMID: 21940754 [PubMed - indexed for MEDLINE] PMCID: PMC3198961