This Article Full Text Full Text (PDF) Supplementary Data Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Debes, J. D. Articles by Tindall, D. J. Search for Related Content PubMed PubMed Citation Articles by Debes, J. D. Articles by Tindall, D. J.

p300 Regulates Androgen Receptor–Independent Expression of Prostate-Specific Antigen in Prostate Cancer Cells Treated Chronically with Interleukin-6

¹ Departments of Urology, Biochemistry, and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota and ² Department of Urology, Innsbruck Medical University, Innsbruck, Austria

Requests for reprints: Donald J. Tindall, Departments of Urology, Biochemistry, and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905. Phone: 507-284-8139; Fax: 507-284-2384; E-mail: tindall.donald{at}mayo.edu.

Prostate cancer is the most frequent non–skin cancer in men. Although the mechanisms involved in the progression of prostate cancer are not entirely understood, androgen receptor has been shown to play an important role. Androgen receptor is expressed in both early and late-stage prostate cancer. Also, androgen-regulated pathways are thought to be active as evidenced by elevated levels of prostate-specific antigen (PSA). In addition, several androgen receptor coactivators and cytokines are involved in prostate cancer progression. In this regard, we have shown previously that the coactivator p300 plays a major role in the androgen-independent activation of PSA by interleukin 6 (IL-6), a cytokine involved in late-stage prostate cancer. In this study, we investigated the role of p300 and its homologue CREB-binding protein in prostate cancer cells treated chronically with IL-6. We found that p300 but not CREB-binding protein induced activation of PSA in these cells and that the histone acetyltransferase activity of p300 was critical. This effect was independent of the presence of androgens or antiandrogens. Moreover, we found markedly reduced levels of androgen receptor in these cells and p300 transfection did not affect those levels, suggesting that the p300 effect on PSA could be bypassing the androgen receptor. Transfection with exogenous androgen receptor showed minimal response of PSA to androgens but higher response to p300. We found similar effects of p300 on the androgen response element III, which mediates the androgen receptor–dependent activation of PSA. Finally, we showed that p300 alone regulates expression of the endogenous PSA gene in the IL-6–treated cells. These findings reveal a new insight in the progression of prostate cancer, suggesting that coactivators, such as p300, play more important roles in late-stage prostate cancer, and could regulate androgen-dependent genes in the absence or with very low levels of androgen receptor.

This article has been cited by other articles:

				S. A Boorjian, H. V Heemers, I. Frank, S. A Farmer, L. J Schmidt, T. J Sebo, and D. J Tindall Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder Endocr. Relat. Cancer, March 1, 2009; 16(1): 123 - 137. [Abstract] [Full Text] [PDF]

				B. Feng, S. Chen, J. Chiu, B. George, and S. Chakrabarti Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1119 - E1126. [Abstract] [Full Text] [PDF]

				H. V. Heemers, K. M. Regan, S. M. Dehm, and D. J. Tindall Androgen Induction of the Androgen Receptor Coactivator Four and a Half LIM Domain Protein-2: Evidence for a Role for Serum Response Factor in Prostate Cancer Cancer Res., November 1, 2007; 67(21): 10592 - 10599. [Abstract] [Full Text] [PDF]

				S. M. Dehm, K. M. Regan, L. J. Schmidt, and D. J. Tindall Selective Role of an NH2-Terminal WxxLF Motif for Aberrant Androgen Receptor Activation in Androgen Depletion Independent Prostate Cancer Cells Cancer Res., October 15, 2007; 67(20): 10067 - 10077. [Abstract] [Full Text] [PDF]

				A. P. Kumar, S. Bhaskaran, M. Ganapathy, K. Crosby, M. D. Davis, P. Kochunov, J. Schoolfield, I-T. Yeh, D. A. Troyer, and R. Ghosh Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a Phellodendron Amurense Bark Extract Clin. Cancer Res., May 1, 2007; 13(9): 2784 - 2794. [Abstract] [Full Text] [PDF]

				H. V. Heemers, T. J. Sebo, J. D. Debes, K. M. Regan, K. A. Raclaw, L. M. Murphy, A. Hobisch, Z. Culig, and D. J. Tindall Androgen Deprivation Increases p300 Expression in Prostate Cancer Cells Cancer Res., April 1, 2007; 67(7): 3422 - 3430. [Abstract] [Full Text] [PDF]

				R. Jasavala, H. Martinez, J. Thumar, A. Andaya, A.-C. Gingras, J. K. Eng, R. Aebersold, D. K. Han, and M. E. Wright Identification of Putative Androgen Receptor Interaction Protein Modules: Cytoskeleton and Endosomes Modulate Androgen Receptor Signaling in Prostate Cancer Cells Mol. Cell. Proteomics, February 1, 2007; 6(2): 252 - 271. [Abstract] [Full Text] [PDF]

				S. M. Dehm and D. J. Tindall Ligand-independent Androgen Receptor Activity Is Activation Function-2-independent and Resistant to Antiandrogens in Androgen Refractory Prostate Cancer Cells J. Biol. Chem., September 22, 2006; 281(38): 27882 - 27893. [Abstract] [Full Text] [PDF]

				L. Wallner, J. Dai, J. Escara-Wilke, J. Zhang, Z. Yao, Y. Lu, M. Trikha, J. A. Nemeth, M. H. Zaki, and E. T. Keller Inhibition of Interleukin-6 with CNTO328, an Anti-Interleukin-6 Monoclonal Antibody, Inhibits Conversion of Androgen-Dependent Prostate Cancer to an Androgen-Independent Phenotype in Orchiectomized Mice. Cancer Res., March 15, 2006; 66(6): 3087 - 3095. [Abstract] [Full Text] [PDF]

				H. I. Scher and C. L. Sawyers Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis J. Clin. Oncol., November 10, 2005; 23(32): 8253 - 8261. [Abstract] [Full Text] [PDF]