Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, OH 43614, USA.
Oncogene. 2010 Feb 4;29(5):723-38. doi: 10.1038/onc.2009.373. Epub 2009 Nov 9.
Nuclear expression of CCAAT enhancer binding protein-alpha (C/EBPalpha), which supports tissue differentiation through several antiproliferative protein-protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPalpha is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPalpha acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen receptor (AR), but this is paradoxical as the genotropic actions of AR are crucial not only for the growth of the prostate but also for its maintenance and function. We show that DNA-bound C/EPBalpha recruits AR to activate transcription. C/EBPalpha-dependent trans-activation by AR also overrode suppression of AREs by C/EBPalpha elsewhere in a promoter. This mechanism was remarkable in that its androgen dependence was apparently for nuclear translocation of AR; it was otherwise androgen independent, flutamide insensitive and tolerant to disruption of AR dimerization. Gene response profiles and global chromatin associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBPalpha. This unique mechanism explains the functional coordination between AR and C/EPBalpha in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.
CCAAT 增强子结合蛋白-α（C/EBPα）的核表达支持通过几种抗增殖蛋白-蛋白相互作用的组织分化，预示着前列腺上皮细胞的终末分化。C/EBPα 也是一种肿瘤抑制因子，但在许多肿瘤中，其抗增殖相互作用可能会因去磷酸化而减弱。C/EBPα 作为雄激素受体（AR）介导的经典雄激素反应元件（ARE）介导的基因激活的核心抑制剂，但这是矛盾的，因为 AR 的基因作用不仅对前列腺的生长至关重要，而且对其维持和功能也至关重要。我们表明，与 DNA 结合的 C/EBPα 招募 AR 来激活转录。AR 的 C/EBPα 依赖性转录激活也克服了 C/EBPα 在启动子其他部位对 ARE 的抑制。这种机制非常显著，因为它的雄激素依赖性显然是 AR 的核易位；否则，它与雄激素无关，对氟他胺不敏感，并且能够耐受 AR 二聚化的破坏。基因反应谱和原位全染色质关联支持 C/EBPα 对 AR 转录信号的直接双模态调节。这种独特的机制解释了 AR 和 C/EBPα 在前列腺中的功能协调，也表明前列腺癌中激素难治性 AR 信号可能通过受体固定发生。
