This Article Full Text Full Text (PDF) 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 Link, K. A. Articles by Knudsen, K. E. Search for Related Content PubMed PubMed Citation Articles by Link, K. A. Articles by Knudsen, K. E.

Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity

Departments of ¹ Cancer Biology and ² Urology, and ³ Kimmel Cancer Center, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania; ⁴ Department of Molecular Cell Biology, University of Leuven, Leuven, Belgium; and ⁵ Department of Pathology, University of Utah, Salt Lake City, Utah

Requests for reprints: Karen E. Knudsen, Department of Cancer Biology, and Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107. Phone: 215-503-8574; Fax: 215-503-8574; E-mail: Karen.Knudsen{at}kimmelcancercenter.org.

Key Words: prostate cancer • androgen receptor • SWI/SNF • BAF57 • chromatin remodeling

The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligand-binding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonist-induced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer. [Cancer Res 2008;68(12):4551–8]

This article has been cited by other articles:

				B. Weissman and K. E. Knudsen Hijacking the Chromatin Remodeling Machinery: Impact of SWI/SNF Perturbations in Cancer Cancer Res., November 1, 2009; 69(21): 8223 - 8230. [Abstract] [Full Text] [PDF]

				K. R. Stengel, C. Thangavel, D. A. Solomon, S. P. Angus, Y. Zheng, and E. S. Knudsen Retinoblastoma/p107/p130 Pocket Proteins: PROTEIN DYNAMICS AND INTERACTIONS WITH TARGET GENE PROMOTERS J. Biol. Chem., July 17, 2009; 284(29): 19265 - 19271. [Abstract] [Full Text] [PDF]

				H. Makkonen, M. Kauhanen, V. Paakinaho, T. Jaaskelainen, and J. J. Palvimo Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers Nucleic Acids Res., July 1, 2009; 37(12): 4135 - 4148. [Abstract] [Full Text] [PDF]

				J. X. Zou, L. Guo, A. S. Revenko, C. G. Tepper, A. T. Gemo, H.-J. Kung, and H.-W. Chen Androgen-Induced Coactivator ANCCA Mediates Specific Androgen Receptor Signaling in Prostate Cancer Cancer Res., April 15, 2009; 69(8): 3339 - 3346. [Abstract] [Full Text] [PDF]