DNA methyltransferases: a novel target for prevention and therapy.
DNA methyltransferases: a novel target for prevention and therapy.
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DOI：
10.3389/fonc.2014.00080
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发表时间：
2014
影响因子：
4.7
通讯作者：
Anant S
中科院分区：
文献类型：
--
作者：
Subramaniam D;Thombre R;Dhar A;Anant S
癌症是美国第二大死因。尽管出现了新的靶向药物，并使用了各种治疗组合，但没有一种可用的治疗方案对晚期癌症患者是治愈的。表观遗传改变越来越被认为是癌症治疗发展的有价值的靶点。由DNA甲基转移酶(DNMT)催化的胞嘧啶5位DNA甲基化是哺乳动物主要的表观遗传修饰。DNMT1是负责维持DNA甲基化模式的主要酶，位于复制叉处，负责甲基化新合成的DNA。DNMT2或TRDMT1是最小的哺乳动物DNMT，被认为参与了DNA损伤、DNA重组和突变修复的识别。它只由C-末端结构域组成，不具有调控的N-末端区域。在多种肿瘤组织和细胞系中，DNMTs，尤其是DNMT3b、DNMT3A和DNMT3L的表达水平经常升高，这可能是多种恶性肿瘤中抑癌基因启动子CpG富含甲基化的部分原因。此外，它已被证明在结肠癌干细胞的自我更新和维持中发挥作用，需要在几种癌症中进行研究。抑制DNMT的作用部分是通过增加肿瘤抑制基因的表达来减少肿瘤的形成。因此，DNMT有可能被用作抗癌靶点。饮食中的植物化学物质也抑制DNMT和癌症干细胞；这是预防和治疗许多癌症的一种有希望的方法。
Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.