Metzger Eric, Wissmann Melanie, Yin Na, Müller Judith M, Schneider Robert, Peters Antoine H F M, Günther Thomas, Buettner Reinhard, Schüle Roland
Universitäts-Frauenklinik und Zentrum für Klinische Forschung, Klinikum der Universität Freiburg, Breisacherstrasse 66, 79106 Freiburg, Germany.
Nature. 2005 Sep 15;437(7057):436-9. doi: 10.1038/nature04020. Epub 2005 Aug 3.
Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.
真核生物中的基因调控需要染色质调节蛋白与特定转录因子（如雄激素受体）的协同相互作用。基因激活和抑制由不同赖氨酸残基处的组蛋白甲基化状态特异性调控。在此我们表明，赖氨酸特异性去甲基化酶1（LSD1；也称为BHC110）在正常人类前列腺和前列腺肿瘤中与雄激素受体共定位。LSD1在体外和体内均与雄激素受体相互作用，并刺激雄激素受体依赖性转录。相反，降低LSD1蛋白水平可消除雄激素诱导的转录激活和细胞增殖。染色质免疫沉淀分析表明，雄激素受体和LSD1以配体依赖性方式形成与染色质相关的复合物。LSD1通过使组蛋白H3赖氨酸9（H3-K9）去甲基化来消除抑制性组蛋白标记，从而导致雄激素受体靶基因的去抑制。此外，我们确定帕吉林是LSD1的一种抑制剂。帕吉林可阻断LSD1对H3-K9的去甲基化作用，进而阻断雄激素受体依赖性转录。因此，调节LSD1活性为调控雄激素受体功能提供了一种新策略。在此，我们将抑制性组蛋白标记的去甲基化与雄激素受体依赖性基因激活联系起来，从而提供了一种去甲基化酶控制特定基因表达的机制。
