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Eaf2 and Prostate Cancer
The identification and characterization of androgen-responsive genes in the prostate represents a major research focus in my lab. Androgen action is mediated through the androgen receptor (AR), a protein that regulates the expression of androgen-responsive genes by binding to a specific sequence in the promoter. One such gene that we identified, U19/Eaf2, plays an essential role in both androgen action and prostate cancer progression. Androgens directly induce Eaf2 expression in normal prostate epithelial cells. We observed Eaf2 downregulation and loss of heterozygosity in more than 80% of advanced human prostate cancer specimens examined, indicating that Eaf2 likely blocks prostate cancer progression. Overexpression of Eaf2 induced apoptosis of prostate cancer cell lines, both in vitro and in vivo, while Eaf2 gene knockout in mice resulted in tumors in multiple tissues. These findings demonstrate that Eaf2 indeed functions as a tumor suppressor. Although no prostate cancer was detected in Eaf2 knockout mice, prostate hyperplasia and high-grade PIN (prostatic intraepithelial neoplasia) were observed, further supporting a critical suppressive role for Eaf2 in prostate cancer. Our current research focuses on Eaf2-binding partners and Eaf2-downstream genes to better understand Eaf2 function. In addition, we plan to develop a screen for small molecules that mimic Eaf2 activity to identify novel therapeutic agents for prostate and other cancers.
Androgen Receptor Intracellular Trafficking
Another area of research interest is AR intracellular trafficking in prostate cancer cells, especially in those that are androgen-refractory. In androgen-sensitive prostate cancer cells, AR remains in the cytoplasm in the absence of ligand. The presence of ligand induces nuclear translocation of AR, resulting in the transactivation of androgen-responsive genes. However, in androgen-refractory prostate cancer cells, AR localizes to the nucleus regardless of ligand. Importantly, ligand-independent AR nuclear localization is a prerequisite for AR to undergo ligand-independent activation. As this activation likely plays a critical role in the development of androgen-refractory disease, elucidating the mechanism of AR ligand-independent nuclear localization may provide insights into disease progression. A better understanding of how prostate cancer transforms from an androgen-sensitive to an androgen-refractory state will provide new treatment targets — a vital endeavor, since no curative therapy exists for advanced disease.
Intermittent Androgen Ablation Therapy and 5 alpha-reductase Inhibition
We are also interested in determining whether intermittent androgen ablation therapy (IAAT) of prostate cancer can be enhanced by 5 alpha-reductase inhibition, which blocks the conversion of testosterone to dihydrotestosterone (DHT). Androgen ablation, the most common treatment for advanced prostate cancer, lessens symptoms and reduces tumor size. Unfortunately though, the vast majority of patients eventually develop lethal androgen-refractory tumors. As intermittent recovery of androgens can promote differentiation of prostate epithelial cells, the hope was that IAAT would slow the progression to androgen-refractory disease. However, the advantage of inducing differentiation is compromised by the disadvantage of androgenic induction of prostate cancer cell proliferation. We previously found that testosterone is more potent than DHT in inducing differentiation and weaker in stimulating proliferation during prostate regrowth. Thus, we investigated the effects of inhibiting the conversion of testosterone. Our preliminary data indicated that inhibition of 5 alpha-reductase can promote the expression of tumor-suppressive, androgen-responsive genes during the regrowth of normal or cancerous prostates in castrated mice. The enhanced expression of tumor-suppressive, androgen-responsive genes should retard tumor regrowth. Accordingly, using an androgen-sensitive human prostate xenograft tumor as a model, we showed that the 5 alpha-reductase inhibitor, finasteride, enhanced the efficacy of IAAT. We are establishing collaborations with medical oncologists, urologists, and pathologists to evaluate whether 5 alpha-reductase inhibitors can enhance IAAT in a clinical trial.
Selected Publications
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.
2. 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.
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. Xiao, W., Ai, J., Habermacher, G., Volpert, O., Yang, X., Zhang, A., Hahn, J., Cai, X., and Wang, Z. U19/Eaf2 binds to and stabilizes von Hippel-Lindau protein. Cancer Research, 69:2599-2606, 2009. PMCID: PMC2806597
5. Su, F., Pascal, LE, Xiao W., and Wang Z. Tumor Suppressor U19/EAF2 Regulates Thrombospondin-1 Expression via p53. Oncogene, 29:(3):421-31, 2010. PMCID: PMC2809809
6. Ai, J., Wang, Y., Dar, J.A., Liu, J., Liu, L., Nelson, J., and Wang, Z. HDAC6 Regulates Androgen Receptor Hypersensitivity and Nuclear Localization via Modulating Hsp90 Acetylation in Castration-Resistant Prostate Cancer. Mol Endocrinol, 23: 1963-1972, 2009 PMCID: PMC2796151
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