This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-2216v1 69/3/958    most recent 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 Welsbie, D. S. Articles by Sawyers, C. L. Search for Related Content PubMed PubMed Citation Articles by Welsbie, D. S. Articles by Sawyers, C. L.

Histone Deacetylases Are Required for Androgen Receptor Function in Hormone-Sensitive and Castrate-Resistant Prostate Cancer

¹ David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California and ² Human Oncology and Pathogenesis Program, ³ Howard Hughes Medical Institute, and ⁴ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, Box 20, 1275 York Avenue, New York, NY 10065. Phone: 646-888-2138; Fax: 646-888-2595; E-mail: sawyersc{at}mskcc.org.

Key Words: prostate cancer • androgen receptor • histone deacetylase

Transcriptional activity of the androgen receptor (AR) is crucial for growth and survival of prostate cancer even upon development of resistance to androgen ablation and antiandrogen therapies. Therefore, novel therapies that can suppress AR transcriptional activity when conventional hormone therapies fail are needed. Here, we show that histone deacetylase (HDAC) inhibitors, including SAHA (vorinostat) and LBH589, which are currently being tested in clinic, could be such a therapy. HDAC inhibitors block the AR-mediated transcriptional activation of many genes, including the TMPRSS2 gene involved in fusion with ETS family members in a majority of prostate cancers. Genetic knockdown of either HDAC1 or HDAC3 can also suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment. Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells, we show that independent of AR protein levels, HDAC inhibitors block AR activity through inhibiting the assembly of coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in castration-resistant prostate cancer models and, therefore, merit clinical investigation in this setting. The HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition. [Cancer Res 2009;69(3):958–66]

This article has been cited by other articles:

				K. E. Knudsen and H. I. Scher Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer Clin. Cancer Res., August 1, 2009; 15(15): 4792 - 4798. [Abstract] [Full Text] [PDF]

				L. R. Molife, G. Attard, P. C. Fong, V. Karavasilis, A. H. M. Reid, S. Patterson, C. E. Riggs Jr, C. Higano, W. M. Stadler, W. McCulloch, et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC) Ann. Onc., July 16, 2009; (2009) mdp270v1. [Abstract] [Full Text] [PDF]

				D. S. Schrump Cytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical Implications Clin. Cancer Res., June 15, 2009; 15(12): 3947 - 3957. [Abstract] [Full Text] [PDF]