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Androgen Deprivation Increases p300 Expression in Prostate Cancer Cells

¹ Departments of Urology/Biochemistry and Molecular Biology and ² Laboratory Medicine/Pathology, Mayo Clinic, Rochester, Minnesota; ³ Department of Urology, General Hospital Feldkirch, Feldkirch, Austria; and ⁴ Department of Urology, Innsbruck Medical University, Innsbruck, Austria

Requests for reprints: Donald J. Tindall, Department of Urology/Biochemistry and Molecular Biology, Mayo Clinic, Guggenheim 1742, 200 1st Street SW, Rochester, MN 55905. Phone: 507-284-8138; Fax: 507-284-2384; E-mail: tindall.donald{at}mayo.edu.

Standard therapy for nonorgan confined prostate cancer aims to block the production or action of androgens. Although initially successful, antiandrogen therapy eventually fails and androgen depletion independent (ADI) disease emerges. Remarkably, ADI prostate cancers still rely on a functional androgen receptor (AR). Aberrant expression of coregulatory proteins required for the formation of productive AR transcriptional complexes is critical for ADI AR activation. Previously, we have shown that the transcriptional coactivator p300 is required for ADI activation of the AR and is up-regulated in prostate cancer, in which its expression is associated with cell proliferation and predicts aggressive tumor features. The mechanism responsible for the deregulated expression of p300, however, remains elusive. Here, we show that p300 expression in prostate cancer cells is subject to androgen regulation. In several prostate cancer model systems, addition of synthetic and natural androgens led to decreased expression of p300 in a time-dependent and dose-dependent manner. Experiments using AR antagonists or small interfering RNA targeting the AR revealed that down-regulation of p300 depends entirely on the presence of a functional AR. It is noteworthy that androgens down-regulated p300 protein expression while leaving messenger levels unaltered. Conversely, both short-term and long-term androgen deprivation resulted in marked up-regulation of p300 expression. The androgen deprivation–induced increase in p300 expression was not affected by the addition of cytokines or growth factors or by cotreatment with antiandrogens. Moreover, increased p300 expression upon androgen starvation is crucial for prostate cancer cell proliferation, as loss of p300 expression severely reduces expression of cyclins governing G₁-S and G₂-M cell cycle transition and decreases 5-bromo-2'-deoxyuridine incorporation. [Cancer Res 2007;67(7):3422–30]

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