KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes.
KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes.
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DOI：
10.1016/j.chembiol.2015.08.007
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发表时间：
2015-09-17
影响因子：
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通讯作者：
Liu ZP
中科院分区：
文献类型：
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作者：
Duan L;Rai G;Roggero C;Zhang QJ;Wei Q;Ma SH;Zhou Y;Santoyo J;Martinez ED;Xiao G;Raj GV;Jadhav A;Simeonov A;Maloney DJ;Rizo J;Hsieh JT;Liu ZP
组蛋白赖氨酸去甲基酶KDM4/JMJD2在包括前列腺癌(PCa)在内的许多人类肿瘤中过表达。KDM4是雄激素受体(AR)的共同激活剂，因此是潜在的治疗靶点。然而，到目前为止，还没有开发出在体内具有抗前列腺癌活性的KDM4抑制剂。在此，我们报道了三种新型KDM4抑制剂(A1、I9和B3)的抗肿瘤作用及其分子机制。这些抑制剂抑制了AR和BMYB调节基因的转录。化合物B3对多种癌细胞株具有很高的选择性，包括缺乏AR的PC3细胞。B3对PC3细胞来源的肿瘤和体外培养的人前列腺癌组织块生长有抑制作用。我们发现了KDM4B激活Polo-like kinase1(PLK1)转录的新机制。B3阻断了KDM4B与PLK1启动子的结合。我们的研究为前列腺癌和KDM4B/PLK1表达升高的肿瘤提供了一种潜在的基于机制的治疗策略。
Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggested a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.