Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
J Steroid Biochem Mol Biol. 2010 Jan;118(1-2):51-8. doi: 10.1016/j.jsbmb.2009.09.017. Epub 2009 Oct 6.
Aryl hydrocarbon receptor (AhR) ligands modulate androgen receptor (AR) signaling in prostate cancer cells through partially defined mechanisms. Furthermore, these facilitatory and inhibitory effects of AhR on AR signaling appear to be cell or context specific. In the present study we demonstrate that both AhR and AhR-nuclear translocator (ARNT) interact with AR. AhR but not ARNT enhanced the AR-transcriptional activity which was independent of exogenous AhR ligand treatment (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). We then tested if coactivators common to both receptors alter the facilitatory effect of AhR on AR activity. NcoA4 overexpression did not alter the AhR facilitatory effect on AR, whereas SRC1 overexpression further enhanced the effect. In contrast, FHL2 overexpression blocked the facilitatory effect of AhR. In the presence of exogenous FHL2 expression, AhR repressed AR activity, whereas at low endogenous levels of FHL2 expression, AhR overexpression enhanced AR activity. At high FHL2 expression levels, TCDD treatment decreased AR activity and this effect was reversed by AhR overexpression. These findings demonstrate that AhR modulation of AR activity is differentially altered by the level of FHL2 and AhR present in the cell.
芳基烃受体 (AhR) 配体通过部分定义的机制调节前列腺癌细胞中的雄激素受体 (AR) 信号。此外，AhR 对 AR 信号的这些促进和抑制作用似乎是细胞或环境特异性的。在本研究中，我们证明 AhR 和 AhR-核转位蛋白 (ARNT) 都与 AR 相互作用。AhR 但不是 ARNT 增强了 AR 的转录活性，这与外源性 AhR 配体处理（2,3,7,8-四氯二苯并对二恶英，TCDD）无关。然后，我们测试了两个受体共有的辅助因子是否改变 AhR 对 AR 活性的促进作用。NcoA4 的过表达并没有改变 AhR 对 AR 的促进作用，而 SRC1 的过表达则进一步增强了这种作用。相比之下，FHL2 的过表达阻断了 AhR 的促进作用。在外源 FHL2 表达的存在下，AhR 抑制了 AR 活性，而在低水平的内源性 FHL2 表达下，AhR 的过表达增强了 AR 活性。在高 FHL2 表达水平下，TCDD 处理降低了 AR 活性，而 AhR 的过表达逆转了这种效应。这些发现表明，AhR 对 AR 活性的调节作用因细胞中存在的 FHL2 和 AhR 的水平而异。
