Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties.
Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties.
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DOI：
10.1158/0008-5472.can-11-0896
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发表时间：
2011-12-01
期刊：
影响因子：
11.2
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Wang J;Lu F;Ren Q;Sun H;Xu Z;Lan R;Liu Y;Ward D;Quan J;Ye T;Zhang H
组蛋白修饰决定了基因表达的表观遗传模式，组蛋白H3在赖氨酸4（H3 K4）的甲基化通常与活性启动子相关。LSD 1/KDM 1是一种组蛋白脱甲基酶，通过将二甲基化的H3 K4转化为单甲基化和未甲基化的H3 K4来抑制基因表达。LSD 1是后生动物发育所必需的，但其在癌症中的病理生理功能仍然主要是未知的。在这项研究中，我们开发了LSD 1的特异性生物活性小抑制剂，可增强H3 K4甲基化并在体内抑制表观遗传抑制基因。引人注目的是，这些化合物抑制多能癌细胞（包括畸胎瘤、胚胎癌和乳腺癌）或表达干细胞标志物Oct 4和Sox 2的胚胎干细胞的增殖，同时对非多能癌或正常体细胞显示最小的生长抑制作用。RNAi介导的LSD 1表达敲低表型模拟了这些效应，证实了小分子的特异性，并进一步建立了多能癌细胞对LSD 1消融的高度敏感性和选择性。为了支持这些结果，我们发现LSD 1蛋白水平在多能癌细胞和表达Oct 4的人睾丸腺瘤组织中高度升高。使用这些新的化学抑制剂作为探针，我们的研究结果建立了LSD 1和组蛋白H3 K4甲基化作为具有干细胞特性的多能癌细胞中重要的癌症选择性表观遗传靶点。
Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting di-methylated H3K4 to mono- and un-methylated H3K4. LSD1 is essential for metazoan development but its pathophysiological functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2, while displaying minimum growth inhibitory effects on non-pluripotent cancer or normal somatic cells. RNAi-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in pluripotent cancer cells that have stem cell properties.