Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells.
Critical threshold levels of DNA methyltransferase 1 are required to maintain DNA methylation across the genome in human cancer cells.
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DOI：
10.1101/gr.208108.116
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发表时间：
2017-04
期刊：
影响因子：
7
通讯作者：
Baylin SB
中科院分区：
文献类型：
--
作者：
Cai Y;Tsai HC;Yen RC;Zhang YW;Kong X;Wang W;Xia L;Baylin SB
通过抑制 DNA 甲基转移酶 (DNMT) 来逆转 DNA 甲基化异常和相关基因沉默是一种重要的潜在癌症治疗范例。最大限度地发挥这一潜力需要精确定义这些酶如何维持全基因组、癌症特异性 DNA 甲基化。迄今为止，对于三种 DNMT（1、3A 和 3B）如何相互作用以维持癌症中 DNA 甲基化异常的确切了解尚不完全。通过结合遗传和 shRNA 消除策略，我们不仅定义了 DNA 甲基转移酶 1 (DNMT1) 的主导作用，还定义了 3A 和 3B 在全基因组 DNA 甲基化维持中的独特作用。将 DNMT1 降低到阈值水平以下是所有基因组区域（包括基因体和增强子区域）DNA 甲基化最大程度丧失以及最大程度逆转异常启动子 DNA 高甲基化和相关基因沉默以重新表达关键基因所必需的。目前的 DNMT 抑制剂 (DNMTIs) 很难达到患者可耐受剂量的这一阈值。我们表明，新方法，例如减少 DNMT 靶向蛋白 UHRF1，可以增强现有 DNA 甲基化抑制剂的 DNA 去甲基化能力，从而充分发挥其治疗潜力。
Reversing DNA methylation abnormalities and associated gene silencing, through inhibiting DNA methyltransferases (DNMTs) is an important potential cancer therapy paradigm. Maximizing this potential requires defining precisely how these enzymes maintain genome-wide, cancer-specific DNA methylation. To date, there is incomplete understanding of precisely how the three DNMTs, 1, 3A, and 3B, interact for maintaining DNA methylation abnormalities in cancer. By combining genetic and shRNA depletion strategies, we define not only a dominant role for DNA methyltransferase 1 (DNMT1) but also distinct roles of 3A and 3B in genome-wide DNA methylation maintenance. Lowering DNMT1 below a threshold level is required for maximal loss of DNA methylation at all genomic regions, including gene body and enhancer regions, and for maximally reversing abnormal promoter DNA hypermethylation and associated gene silencing to reexpress key genes. It is difficult to reach this threshold with patient-tolerable doses of current DNMT inhibitors (DNMTIs). We show that new approaches, like decreasing the DNMT targeting protein, UHRF1, can augment the DNA demethylation capacities of existing DNA methylation inhibitors for fully realizing their therapeutic potential.