Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells.
Synergistic re-activation of epigenetically silenced genes by combinatorial inhibition of DNMTs and LSD1 in cancer cells.
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DOI：
10.1371/journal.pone.0075136
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liang G
中科院分区：
文献类型：
--
作者：
Han H;Yang X;Pandiyan K;Liang G
由异常启动子DNA超甲基化和抑制性组蛋白修饰介导的表观遗传基因沉默是癌症的标志。虽然遗传，动态的性质和潜在的可逆性，通过药物干预，使这种畸变有吸引力的目标。由于癌症含有多种表观遗传异常，因此针对不同缺陷的联合治疗可能会提高其个体疗效。5-氮杂-2 '-脱氧胞苷（5-Aza-CdR）是FDA批准的用于治疗骨髓增生异常综合征的药物，其可以抑制DNA甲基转移酶（DNMT）掺入分裂细胞的DNA中，导致整体去甲基化。最近，第一个组蛋白去甲基化酶，赖氨酸特异性去甲基化酶1（LSD 1），它使组蛋白和非组蛋白底物去甲基化，已成为表观遗传治疗的新靶点。使用clorgyline，一种LSD 1抑制剂（LSD 1 i）治疗癌细胞系，我们表明clorgyline采用两种作用机制，这取决于细胞类型：它可以诱导全局DNA去甲基化或抑制LSD 1驱动的H3 K4 me 2和H3 K4 me 1去甲基化，以建立一个活跃的染色质构型。我们还研究了5-Aza-CdR与氯吉林组合的治疗效果，并确定这种组合治疗通过富集H3 K4 me 2和H3 K4 me 1对重新激活异常沉默的基因具有协同作用。许多重新激活的基因被归类为癌症睾丸抗原或属于干扰素信号通路，这表明免疫治疗的潜在意义。总之，我们的结果表明，由DNMT抑制剂（DNMTi）和LSD 1 i组成的组合治疗具有增强的治疗价值，并且可以提高表观遗传治疗的疗效。
Epigenetic gene silencing, mediated by aberrant promoter DNA hypermethylation and repressive histone modifications, is a hallmark of cancer. Although heritable, the dynamic nature and potential reversibility through pharmacological interventions make such aberrations attractive targets. Since cancers contain multiple epigenetic abnormalities, combining therapies that target different defects could potentially enhance their individual efficacies. 5-Aza-2'-deoxycytidine (5-Aza-CdR), FDA-approved drug for the treatment of myelodysplastic syndrome, can inhibit DNA methyltransferases (DNMTs) upon incorporation into the DNA of dividing cells, resulting in global demethylation. More recently, the first histone demethylase, lysine specific demethylase 1 (LSD1), which demethylates both histone and non-histone substrates, has become a new target for epigenetic therapy. Using, clorgyline, an LSD1 inhibitor (LSD1i) to treat cancer cell lines, we show that clorgyline employs two mechanisms of action depending on the cell type: it can either induce global DNA demethylation or inhibit LSD1-driven H3K4me2 and H3K4me1 demethylation to establish an active chromatin configuration. We also investigate the therapeutic efficacy of combining 5-Aza-CdR with clorgyline and determine that this combinatorial treatment has synergistic effects on reactivating aberrantly silenced genes by enriching H3K4me2 and H3K4me1. Many of the reactivated genes are categorized as cancer testis antigens or belong to the interferon-signaling pathway, suggesting potential implications for immunotherapy. Together, our results demonstrate that combinatorial treatment consisting of a DNMT inhibitor (DNMTi) and an LSD1i have enhanced therapeutic values and could improve the efficacy of epigenetic therapy.
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DOI：
10.1073/pnas.0604602103
发表时间：
2006-09-19
影响因子：
11.1
作者：
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影响因子：
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