Aryl hydrocarbon receptor (AhR) and androgen receptor (AR) are ligand-activated transcription factors with profound cross-talk between their signal transduction pathways. Previous studies have shown that AhR agonists activate the transcription of AR-regulated genes in an androgen-independent manner; however, the underlying mechanism remains unclear. To decipher this mechanism, we evaluated the effects of 3-methylcholanthrene (3MC), a potent AhR agonist, on the transcription of AR-regulated genes in three AR-expressing cell lines. 3MC induced the expression of not only three representative AR-regulated chromosomal genes but also the exogenous AR-responsive luciferase reporter gene. No significant difference in the 3MC-induced luciferase activity was detected in the presence of SKF-525A, a non-specific inhibitor of CYP enzymes. The androgenic effects of 3MC were diminished by AhR and AR knockdown. Following 3MC treatment, the amount of nuclear AhR and AR increased synchronously. Co-immunoprecipitation revealed that AhR and AR formed a complex in the nucleus of cells treated with 3MC. AR was recruited to the proximal promoter and distal enhancer regions of the PSA gene upon the addition of 3MC. We propose that AhR activated by 3MC forms a complex with unliganded AR which translocates from the cytoplasm to the nucleus. Nuclear AR now binds the transcriptional regulatory region of AR-regulated genes and activates the transcription.

中文翻译：

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潜在的芳基烃受体激动剂3-甲基胆甾醇的雄激素作用基础为非雄激素依赖性机制。

芳烃受体（AhR）和雄激素受体（AR）是配体激活的转录因子，在它们的信号转导途径之间存在很深的串扰。先前的研究表明，AhR激动剂以一种与雄激素无关的方式激活AR调控基因的转录。但是，其潜在机制仍不清楚。为了破译这种机制，我们评估了一种有效的AhR激动剂3-甲基胆甾醇（3MC）对三种表达AR的细胞中AR调控基因转录的影响。3MC不仅诱导了三个代表性的AR调控的染色体基因的表达，而且还诱导了外源性的AR反应性荧光素酶报道基因的表达。在SKF-525A（一种非CYP酶抑制剂）的存在下，未检测到3MC诱导的荧光素酶活性的显着差异。3R的抗雄激素作用可被AhR和AR抑制作用减弱。经过3MC处理，核AhR和AR的量同步增加。免疫共沉淀显示AhR和AR在3MC处理的细胞核中形成复合物。AR被募集到AR的近端启动子和远端增强子区域添加3MC后的PSA基因。我们建议由3MC激活的AhR与未配体的AR形成复合物，该配体从细胞质转移到细胞核。现在，核AR结合AR调控基因的转录调控区域并激活转录。