Transcriptional Selectivity of Epigenetic Therapy in Cancer.
Transcriptional Selectivity of Epigenetic Therapy in Cancer.
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癌症表观遗传治疗的转录选择性。
DOI：
10.1158/0008-5472.can-16-0834
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发表时间：
2017-01-15
期刊：
影响因子：
11.2
通讯作者：
Issa JJ
中科院分区：
文献类型：
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作者：
Sato T;Cesaroni M;Chung W;Panjarian S;Tran A;Madzo J;Okamoto Y;Zhang H;Chen X;Jelinek J;Issa JJ
表观遗传癌症治疗发展的一个核心挑战是能够直接选择性地调节基因表达以实现疾病选择性疗效。为了解决这个问题，我们利用RNA-seq、DNA甲基化和ChIP-seq分析了一组结肠癌、乳腺癌和白血病细胞系对DNA甲基转移酶（DAC）、组蛋白去乙酰化酶（Depsi）、组蛋白去甲基化酶（KDM1A抑制剂S2101）和组蛋白甲基化酶（EHMT2抑制剂UNC0638和EZH2抑制剂GSK343）的小分子抑制剂的表观遗传反应。我们还描述了DAC与其他化合物结合的效果。在采用的癌细胞模型中，我们发现DAC影响8.6%的转录组，95.4%的受影响基因上调。DAC优先调节在癌症中沉默的基因和在启动子处甲基化的基因。相比之下，Depsi影响了30.4%的转录组的表达，但对基因上调或沉默基因的选择性很小。S2101、UNC0638和GSK343仅影响2%的转录组，其中UNC0638和GSK343分别优先靶向标记为H3K9me2或H3K27me3的基因。当与组蛋白甲基化酶抑制剂联合使用时，DAC的基因上调程度得到扩展，同时仍然保持对DNA甲基化基因和沉默基因的选择性。然而，联合治疗上调的基因表现出有限的重叠，表明基于不同的表观遗传治疗组合靶向不同的基因组的可能性。总体而言，我们的研究结果表明，DNA甲基转移酶抑制剂优先靶向癌症相关基因，并且可以与靶向组蛋白甲基化的抑制剂联合使用以产生协同效应，同时仍保持选择性。
A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation and ChIP-seq analyses the epigenetic response of a set of colon, breast and leukemia cancer cell lines to small molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343). We also characterized the effects of DAC as combined with the other compounds. Averaged over the cancer cell models employed, we found that DAC affected 8.6% of the transcriptome and that 95.4% of the genes affected were upregulated. DAC preferentially regulated genes that were silenced in cancer and that were methylated at their promoters. In contrast, Depsi affected the expression of 30.4% of the transcriptome but showed little selectivity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 affected only 2% of the transcriptome, with UNC0638 and GSK343 preferentially targeting genes marked with H3K9me2 or H3K27me3, respectively. When combined with histone methylase inhibitors, the extent of gene upregulation by DAC was extended while still maintaining selectivity for DNA methylated genes and silenced genes. However, the genes upregulated by combination treatment exhibited limited overlap, indicating the possibility of targeting distinct sets of genes based on different epigenetic therapy combinations. Overall, our results demonstrated that DNA methyltransferase inhibitors preferentially target cancer-relevant genes and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining selectivity.