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首页> 外文期刊>Amino acids >Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSDl) and altering chromatin structure in human breast cancer cells
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Polyamine analogs modulate gene expression by inhibiting lysine-specific demethylase 1 (LSDl) and altering chromatin structure in human breast cancer cells

机译：多胺类似物通过抑制赖氨酸特异性脱甲基酶1（LSD1）和改变人类乳腺癌细胞中的染色质结构来调节基因表达

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摘要

Aberrant epigenetic repression of gene expression has been implicated in most cancers, including breast cancer. The nuclear amine oxidase, lysine-specific demethylase 1 (LSDl) has the ability to broadly repress gene expression by removing the activating mono- and di-methylation marks at the lysine 4 residue of histone 3 (H3K4mel and me2). Additionally, LSD1 is highly expressed in estrogen receptor a negative (ER-) breast cancer cells. Since epigenetic marks are reversible, they make attractive therapeutic targets. Here we examine theeffects of polyamine analog inhibitors of LSDl on gene expression, with the goal of targeting LSDl as a therapeutic modality in the treatment of breast cancer. Exposure of the ER-negative human breast cancer cells, MDA-MB-231 to the LSDl inhibitors, 2d or PG11144, significantly increases global H3K4mel and H3K4me2, and alters gene expression. Array analysis indicated that 98 (75 up and 23 down) and 477 (237 up and 240 down) genes changed expression by at least 1.5-fold or greater after treatment with 2d and PG11144, respectively. The expression of 12 up-regulated genes by 2d and 14 up-regulated genes by PG11144 was validated by quantitative RT-PCR. Quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated that up-regulated gene expression by polyamine analogs is associated with increase of the active histone marks H3K4mel, H3K4me2 and H3K9act, and decrease of the repressive histone marks H3K9me2 and H3K27me3, in the promoter regions of the relevant target genes. These data indicate that the pharmacologic inhibition of LSDl can effectively alter gene expression and that this therapeutic strategy has potential.
机译：基因表达的异常表观遗传抑制与大多数癌症有关，包括乳腺癌。核胺氧化酶赖氨酸特异性脱甲基酶1（LSD1）具有通过去除组蛋白3（H3K4mel和me2）的赖氨酸4残基处的活化单甲基和二甲基化标记来广泛抑制基因表达的能力。此外，LSD1在雌激素受体阴性（ER-）乳腺癌细胞中高表达。由于表观遗传标记是可逆的，因此它们可以作为有吸引力的治疗靶标。在这里，我们检查了LSD1的多胺类似物抑制剂对基因表达的影响，目的是将LSD1靶向作为治疗乳腺癌的一种治疗方式。 ER阴性的人类乳腺癌细胞MDA-MB-231暴露于LSD1抑制剂2d或PG11144，会显着增加整体H3K4mel和H3K4me2，并改变基因表达。阵列分析表明，分别用2d和PG11144处理后，有98个基因（75个向上和23个向下）和477个基因（237个向上和240个向下）使表达改变至少1.5倍或更多。通过定量RT-PCR验证了2d的12个上调基因和PG11144的14个上调基因的表达。定量染色质免疫沉淀（ChIP）分析表明，在相关启动子区域中，多胺类似物上调的基因表达与活性组蛋白标记H3K4mel，H3K4me2和H3K9act的增加以及抑制性组蛋白标记H3K9me2和H3K27me3的减少有关靶基因。这些数据表明，LSD1的药理学抑制作用可以有效地改变基因表达，并且这种治疗策略具有潜力。

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