Epigenetic silencing of the MGMT gene in cancer
Epigenetic silencing of the MGMT gene in cancer
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DOI：
10.1139/o05-140
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发表时间：
2005-08-01
影响因子：
2.9
通讯作者：
Mukai, T
中科院分区：
文献类型：
--
作者：
Soejima, H;Zhao, W;Mukai, T
O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)基因的沉默是DNA修复的关键，在癌症的发生发展中起着关键作用。基因产物功能正常，会从致突变的O-6-甲基鸟嘌呤中去除一个甲基，O-6-甲基鸟嘌呤是由烷化剂产生的，可能与胸腺嘧啶不匹配，通过DNA复制导致过渡性突变。在多种人类肿瘤中，MGMT在表观遗传学上是沉默的。众所周知，启动子CpG岛上的DNA高甲基化在肿瘤抑制基因的表观遗传沉默中起着关键作用。然而，在一些癌细胞中，MGMT沉默发生在DNA高甲基化的情况下。组蛋白H3赖氨酸9的二甲基化和甲基CpG结合蛋白的结合在MGMT沉默的细胞中是常见和必要的。当使用烷化剂时，MGMT沉默被证明是一个较差的预后因素，但却是一个很好的化疗预测标记物。在这篇综述中，我们描述了MGMT沉默的最新进展及其在癌症发生中的作用；表观遗传学机制；以及临床意义。
Silencing of the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a key to DNA repair, plays a critical role in the development of cancer. The gene product, functioning normally, removes a methyl group from mutagenic O-6-methylguanine, which is produced by alkylating agents and can make a mismatched pair with thymine, leading to transition mutation through DNA replication. MGMT is epigenetically silenced in various human tumors. It is well known that DNA hypermethylation at the promoter CpG island plays a pivotal role in the epigenetic silencing of tumor suppressor genes. MGMT silencing, however, occurs without DNA hypermethylation in some cancer cells. Dimethylation of histone H3 lysine 9 and binding of methyl-CpG binding proteins are common and essential in MGMT-silenced cells. Silencing of MGMT has been shown to be a poor prognostic factor but a good predictive marker for chemotherapy when alkylating agents are used. In this review, we describe recent advances in understanding the silencing of MGMT and its role in carcinogenesis; epigenetic mechanisms; and clinical implications.