Yang Shan-Zhong, Abdulkadir Sarki A
Department of Pathology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294, USA.
J Biol Chem. 2003 Oct 10;278(41):39906-11. doi: 10.1074/jbc.M307250200. Epub 2003 Jul 30.
The transcription factor early growth response gene 1 (EGR1) has been implicated in diverse roles in the regulation of cell growth, apoptosis, and differentiation. Previous studies suggest that the effects of EGR1 on tumorigenesis are critically dependent on the cellular context. In a majority of prostate cancers, EGR1 is overexpressed and promotes prostate tumor progression. In contrast, in other tumor types such as breast cancers and glioblastomas, EGR1 is expressed at low levels and when overexpressed can inhibit tumor growth. To explore the role of EGR1 in prostate tumorigenesis, we examined the impact of EGR1 expression on the androgen receptor (AR) signaling pathway. We show here that EGR1 binds to the AR in prostate carcinoma cells, and an EGR1-AR complex can be detected by chromatin immunoprecipitation at the enhancer of an endogenous AR target gene. Overexpression of EGR1 enhanced AR-mediated transactivation, whereas EGR1 knockdown by small interfering RNA inhibited AR signaling pathway activity. Furthermore, Western blot and immunocytochemical analyses showed that constitutive overexpression of EGR1 promotes the translocation of AR from the cytoplasm to the nucleus. These results indicate that EGR1 may promote prostate cancer development by modulating the androgen receptor signaling pathway.
转录因子早期生长反应基因1（EGR1）在细胞生长、凋亡和分化的调控中具有多种作用。先前的研究表明，EGR1对肿瘤发生的影响严重依赖于细胞环境。在大多数前列腺癌中，EGR1过表达并促进前列腺肿瘤进展。相反，在其他肿瘤类型如乳腺癌和胶质母细胞瘤中，EGR1表达水平较低，过表达时可抑制肿瘤生长。为了探究EGR1在前列腺肿瘤发生中的作用，我们检测了EGR1表达对雄激素受体（AR）信号通路的影响。我们在此表明，EGR1在前列腺癌细胞中与AR结合，并且通过染色质免疫沉淀在内源性AR靶基因的增强子处可检测到EGR1-AR复合物。EGR1的过表达增强了AR介导的反式激活，而小干扰RNA介导的EGR1敲低抑制了AR信号通路活性。此外，蛋白质印迹和免疫细胞化学分析表明，EGR1的组成型过表达促进了AR从细胞质向细胞核的转运。这些结果表明，EGR1可能通过调节雄激素受体信号通路促进前列腺癌的发展。
