A coregulatory role for the mediator complex in prostate cancer cell proliferation and gene expression.
A coregulatory role for the mediator complex in prostate cancer cell proliferation and gene expression.
复制标题
DOI：
10.1158/0008-5472.can-06-3039
复制
发表时间：
2007-05
期刊：
影响因子：
11.2
通讯作者：
R. Vijayvargia;Michael May;J. Fondell
中科院分区：
文献类型：
--
作者：
R. Vijayvargia;Michael May;J. Fondell
雄激素受体（AR）信号通路对于前列腺癌细胞的存活和增殖很重要。由于 AR 活性是由不同的共调节因子和复合物促进的，因此可以想象，其中一些蛋白质也可能在促进前列腺肿瘤发生中发挥作用。多亚基介导复合物是包括 AR 在内的多种转录调节因子的重要共激活因子，但其在前列腺癌中的作用尚不清楚。在这里，我们使用 RNA 干扰来敲低前列腺癌细胞中两个完整介体成分 MED1/TRAP220 和 MED17 的表达。 MED1/TRAP220 在雄激素信号传导中发挥着特别重要的作用，因为它是 AR 的直接结合靶标。我们发现任一亚基的敲低都会显着降低瞬时转染的雄激素反应报告基因的转录，并抑制内源性 AR 靶基因的雄激素依赖性表达。我们首次表明，前列腺癌细胞中 MED1/TRAP220 或 MED17 的缺失显着降低雄激素依赖性和非依赖性细胞增殖，抑制细胞周期进程并增加细胞凋亡。此外，我们发现 MED1/TRAP220 在 AR 阳性和阴性前列腺癌细胞系以及我们检查的 50%（20 例中的 10 例）临床局限性人类前列腺癌中均过表达，因此表明 MED1/TRAP220 过度活跃可能与前列腺肿瘤发生有关。总之，我们的数据表明 Mediator 在前列腺癌细胞增殖和存活中发挥重要的共同调节作用，因此可能代表治疗干预的新靶点。
Androgen receptor (AR) signaling pathways are important for the survival and proliferation of prostate cancer cells. Because AR activity is facilitated by distinct coregulatory factors and complexes, it is conceivable that some of these proteins might also play a role in promoting prostate oncogenesis. The multisubunit Mediator complex is an important coactivator for a broad range of regulatory transcriptional factors including AR, yet its role in prostate cancer is unclear. Here, we used RNA interference to knock down the expression of two integral Mediator components, MED1/TRAP220 and MED17, in prostate cancer cells. MED1/TRAP220 plays a particularly important role in androgen signaling in that it serves as a direct binding target for AR. We found that the knockdown of either subunit markedly decreases transcription from transiently transfected androgen-responsive reporter genes, as well as inhibits androgen-dependent expression of endogenous AR target genes. We show for the first time that loss of either MED1/TRAP220 or MED17 in prostate cancer cells significantly decreases both androgen-dependent and -independent cellular proliferation, inhibits cell cycle progression, and increases apoptosis. Furthermore, we show that MED1/TRAP220 is overexpressed in both AR-positive and -negative prostate cancer cells lines, as well as in 50% (10 of 20) of the clinically localized human prostate cancers we examined, thus suggesting that MED1/TRAP220 hyperactivity may have implications in prostate oncogenesis. In sum, our data suggest that Mediator plays an important coregulatory role in prostate cancer cell proliferation and survival, and therefore, may represent a new target for therapeutic intervention.