Heemers Hannelore V, Sebo Thomas J, Debes Jose D, Regan Kevin M, Raclaw Kristin A, Murphy Linda M, Hobisch Alfred, Culig Zoran, Tindall Donald J
Departments of Urology/Biochemistry and Molecular Biology and Laboratory Medicine/Pathology, Mayo Clinic, Rochester, Minnesota, USA.
Cancer Res. 2007 Apr 1;67(7):3422-30. doi: 10.1158/0008-5472.CAN-06-2836.
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 G(1)-S and G(2)-M cell cycle transition and decreases 5-bromo-2'-deoxyuridine incorporation.
非器官局限性前列腺癌的标准治疗旨在阻断雄激素的产生或作用。尽管抗雄激素治疗最初取得了成功，但最终还是会失败，雄激素非依赖（ADI）性疾病会出现。值得注意的是，ADI前列腺癌仍然依赖功能性雄激素受体（AR）。形成有活性的AR转录复合物所需的共调节蛋白的异常表达对于ADI AR激活至关重要。此前，我们已经表明转录共激活因子p300是ADI激活AR所必需的，并且在前列腺癌中上调，其表达与细胞增殖相关，并可预测侵袭性肿瘤特征。然而，导致p300表达失调的机制仍然不清楚。在这里，我们表明前列腺癌细胞中p300的表达受雄激素调节。在几个前列腺癌模型系统中，添加合成雄激素和天然雄激素会导致p300表达以时间和剂量依赖性方式降低。使用AR拮抗剂或靶向AR的小干扰RNA进行的实验表明，p300的下调完全依赖于功能性AR的存在。值得注意的是，雄激素下调了p300蛋白表达，而信使水平未改变。相反，短期和长期雄激素剥夺均导致p300表达显著上调。雄激素剥夺诱导的p300表达增加不受细胞因子或生长因子添加或与抗雄激素联合治疗的影响。此外，雄激素饥饿时p300表达增加对前列腺癌细胞增殖至关重要，因为p300表达缺失会严重降低调控G(1)-S和G(2)-M细胞周期转换的细胞周期蛋白的表达，并减少5-溴-2'-脱氧尿苷掺入。
