Teodoridis Jens M, Strathdee Gordon, Brown Robert
Centre for Oncology and Applied Pharmacology, CRUK Beatson Laboratories, Glasgow University, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Drug Resist Updat. 2004 Aug-Oct;7(4-5):267-78. doi: 10.1016/j.drup.2004.06.005.
Many genes become transcriptionally silenced during the development of cancer. As well as affecting disease progression, gene silencing has the potential to influence drug resistance and clinical outcome following therapy. In addition to silencing due to gene mutations, covalent epigenetic modifications such as DNA hypermethylation and histone post-translational modifications are associated with transcriptional inactivation of many genes and are an important early event during carcinogenesis and tumour development. Aberrant methylation of CpG islands in promoters is associated with transcriptional inactivation of genes involved in all aspects of tumour development. Genes involved in key DNA damage response pathways, such as cell cycle control, apoptosis signalling and DNA repair, can frequently become methylated and epigenetically silenced in tumours. This may lead to differences in intrinsic sensitivity of tumours to chemotherapy, depending on the specific function of the gene inactivated. Furthermore, it is proposed that chemotherapy itself can exert a selective pressure on epigenetically silenced drug sensitivity genes present in subpopulations of cells, leading to acquired chemoresistance. Since the DNA sequence of epigenetically inactivated genes are not mutated but rather subject to reversible modifications via DNA methyltransferases (DNMTs) or histone modification, it is possible to reverse silencing using small molecule inhibitors. Such compounds show anti-tumour activity and can increase the sensitivity of drug resistant preclinical tumour models. Clinical trials of epigenetic therapies are now underway. Epigenetic profiling, using DNA methylation and histone analysis, will provide guidance on optimisation of these therapies with conventional chemotherapy and will help identify patient populations who may particularly benefit from such approaches.
许多基因在癌症发展过程中会发生转录沉默。基因沉默不仅会影响疾病进展，还可能影响治疗后的耐药性和临床结果。除了因基因突变导致的沉默外，共价表观遗传修饰，如DNA高甲基化和组蛋白翻译后修饰，与许多基因的转录失活有关，并且是致癌作用和肿瘤发展过程中的一个重要早期事件。启动子中CpG岛的异常甲基化与肿瘤发展各个方面所涉及基因的转录失活有关。参与关键DNA损伤反应途径的基因，如细胞周期控制、凋亡信号传导和DNA修复，在肿瘤中经常会发生甲基化并在表观遗传上沉默。这可能会导致肿瘤对化疗的内在敏感性存在差异，具体取决于失活基因的特定功能。此外，有人提出化疗本身可以对细胞亚群中表观遗传沉默的药物敏感性基因施加选择性压力，从而导致获得性化疗耐药。由于表观遗传失活基因的DNA序列没有发生突变，而是通过DNA甲基转移酶（DNMT）或组蛋白修饰进行可逆修饰，因此有可能使用小分子抑制剂来逆转沉默。这类化合物具有抗肿瘤活性，可以提高耐药临床前肿瘤模型的敏感性。目前正在进行表观遗传治疗的临床试验。利用DNA甲基化和组蛋白分析进行的表观遗传谱分析，将为这些疗法与传统化疗的优化提供指导，并有助于确定可能特别受益于此类方法的患者群体。
