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Androgen Receptor Overexpression in Prostate Cancer Linked to Pur Loss from a Novel Repressor Complex

¹ New York University Cancer Institute, New York, New York; ² Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia; ³ Mount Sinai School of Medicine, New York, New York; and ⁴ Stadtische Kliniken, Offenbach, Germany

Requests for reprints: Anna C. Ferrari, New York University Cancer Institute, New York University School of Medicine, 8th Floor, 160 East 34th Street, New York, NY 10016. Phone: 212-731-5389; Fax: 212-731-5455; E-mail: anna.ferrari{at}nyumc.org.

Key Words: androgen receptor • hormone refractory • transcriptional repressor

Increased androgen receptor (AR) expression and activity are pivotal for androgen-independent (AI) prostate cancer (PC) progression and resistance to androgen-deprivation therapy. We show that a novel transcriptional repressor complex that binds a specific sequence (repressor element) in the AR gene 5'-untranslated region contains Pur and hnRNP-K. Pur expression, its nuclear localization, and its AR promoter association, as determined by chromatin immunoprecipitation analysis, were found to be significantly diminished in AI-LNCaP cells and in hormone-refractory human PCs. Transfection of AI cells with a plasmid that restored Pur expression reduced AR at the transcription and protein levels. Pur knockdown in androgen-dependent cells yielded higher AR and reduced p21, a gene previously shown to be under negative control of AR. These changes were linked to increased proliferation in androgen-depleted conditions. Treatment of AI cells with histone deacetylase and DNA methylation inhibitors restored Pur protein and binding to the AR repressor element. This correlated with decreased AR mRNA and protein levels and inhibition of cell growth. Pur is therefore a key repressor of AR transcription and its loss from the transcriptional repressor complex is a determinant of AR overexpression and AI progression of PC. The success in restoring Pur and the repressor complex function by pharmacologic intervention opens a promising new therapeutic approach for advanced PC. [Cancer Res 2008;68(8):2678–88]