Graduate Institute of Pharmacognosy, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan ; Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan ; Program for Clinical Pharmacogenomics and Pharmacoproteomics, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Department of Pharmacology and Institute of Basic Medical Sciences, National Cheng Kung University, No.1, University Road, Tainan 70101, Taiwan.
Cell Biosci. 2014 Aug 19;4:46. doi: 10.1186/2045-3701-4-46. eCollection 2014.
Cancer is a leading cause of death worldwide. Aberrant promoter hypermethylation of CpG islands associated with tumor suppressor genes can lead to transcriptional silencing and result in tumorigenesis. DNA methyltransferases (DNMTs) are the enzymes responsible for DNA methylation and have been reported to be over-expressed in various cancers. This review highlights the current status of transcriptional and post-translational regulation of the DNMT expression and activity with a focus on dysregulation involved in tumorigenesis. The transcriptional up-regulation of DNMT gene expression can be induced by Ras-c-Jun signaling pathway, Sp1 and Sp3 zinc finger proteins and virus oncoproteins. Transcriptional repression on DNMT genes has also been reported for p53, RB and FOXO3a transcriptional regulators and corepressors. In addition, the low expressions of microRNAs 29 family, 143, 148a and 152 are associated with DNMTs overexpression in various cancers. Several important post-translational modifications including acetylation and phosphorylation have been reported to mediate protein stability and activity of the DNMTs especially DNMT1. In this review, we also discuss drugs targeting DNMT protein expression and activation for therapeutic strategy against cancer.
癌症是全球主要的死亡原因。与肿瘤抑制基因相关的 CpG 岛的启动子异常高甲基化可导致转录沉默，并导致肿瘤发生。DNA 甲基转移酶（DNMTs）是负责 DNA 甲基化的酶，已在各种癌症中报告过度表达。本综述重点介绍了 DNMT 表达和活性的转录和翻译后调节的最新状态，特别关注肿瘤发生中的失调。DNMT 基因表达的转录上调可由 Ras-c-Jun 信号通路、Sp1 和 Sp3 锌指蛋白和病毒癌蛋白诱导。也有报道称 p53、RB 和 FOXO3a 转录调节剂和共抑制剂对 DNMT 基因进行转录抑制。此外，miRNA 家族 29、143、148a 和 152 的低表达与各种癌症中 DNMTs 的过表达有关。已经报道了几种重要的翻译后修饰，包括乙酰化和磷酸化，这些修饰可介导 DNMTs 特别是 DNMT1 的蛋白稳定性和活性。在本综述中，我们还讨论了针对 DNMT 蛋白表达和激活的药物，以作为针对癌症的治疗策略。
