Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor
Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor
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DOI：
10.1002/ijc.27555
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发表时间：
2012-12-01
影响因子：
6.4
通讯作者：
Buettner, Reinhard
中科院分区：
文献类型：
--
作者：
Willmann, Dominica;Lim, Soyoung;Buettner, Reinhard
染色质修饰酶对组蛋白的翻译后修饰调节染色质结构和基因表达。由于组蛋白修饰的放松有助于癌症的进展，抑制染色质修饰酶如组蛋白去甲基化酶是一种有吸引力的治疗策略，以损害癌症的生长。赖氨酸特异性去甲基酶1 （LSD1）去除组蛋白H3赖氨酸4或9的单甲基和二甲基标记。LSD1与雄激素受体（AR）联合控制雄激素依赖性基因表达和前列腺肿瘤细胞增殖，因此突出了LSD1作为药物靶点的作用。通过蛋白质结构相似聚类和体外筛选相结合，我们鉴定了Namoline，一个？吡咯酮是一种新型的、选择性的、可逆的LSD1抑制剂。纳莫啉在体外和体内阻断LSD1去甲基酶活性。Namoline抑制LSD1导致ar调控的基因表达沉默，严重损害体外和体内雄激素依赖性增殖。因此，纳莫啉是一种新的有前途的起始化合物，用于治疗雄激素依赖性前列腺癌。
Post-translational modifications of histones by chromatin modifying enzymes regulate chromatin structure and gene expression. As deregulation of histone modifications contributes to cancer progression, inhibition of chromatin modifying enzymes such as histone demethylases is an attractive therapeutic strategy to impair cancer growth. Lysine-specific demethylase 1 (LSD1) removes mono- and dimethyl marks from lysine 4 or 9 of histone H3. LSD1 in association with the androgen receptor (AR) controls androgen-dependent gene expression and prostate tumor cell proliferation, thus highlighting LSD1 as a drug target. By combining protein structure similarity clustering and in vitro screening, we identified Namoline, a ?-pyrone, as a novel, selective and reversible LSD1 inhibitor. Namoline blocks LSD1 demethylase activity in vitro and in vivo. Inhibition of LSD1 by Namoline leads to silencing of AR-regulated gene expression and severely impairs androgen-dependent proliferation in vitro and in vivo. Thus, Namoline is a novel promising starting compound for the development of therapeutics to treat androgen-dependent prostate cancer.