Grønbaek Kirsten, Treppendahl Marianne, Asmar Fazila, Guldberg Per
Department of Haematology, Rigshospitalet, Copenhagen, Denmark.
Basic Clin Pharmacol Toxicol. 2008 Nov;103(5):389-96. doi: 10.1111/j.1742-7843.2008.00325.x.
Epigenetic silencing of gene transcription by methylation of DNA or modification of histones is a key event in neoplastic initiation and progression. Alterations of the epigenome have been identified in virtually all types of cancer and involve multiple genes and molecular pathways. Recent studies have suggested that epigenetic gene inactivation may represent the first step in tumorigenesis, possibly by affecting the normal differentiation of stem cells and by predisposing these cells to additional oncogenic insults. The mechanisms that drive epigenetic silencing in pre-malignant cells are still unknown, but may reflect simple stochastic events that are beneficial to cancer precursor cells. It is now well established that epigenetically silenced genes may be reactivated pharmacologically. Some inhibitors of DNA methyltransferases (5-aza-cytidine and 5-aza-2'-deoxycytidine) or histone deacetylases (vorinostat) have been approved for clinical use by the US Food and Drug Administration and have reached clinical phase III trials elsewhere. The prospect that epigenetic alterations may play an essential role in renewing and maintaining the malignant clone has opened up new perspectives for the use of epigenetic therapy in cancer prevention and maintenance.
DNA甲基化或组蛋白修饰导致的基因转录表观遗传沉默是肿瘤发生和发展的关键事件。几乎在所有类型的癌症中都发现了表观基因组的改变，且涉及多个基因和分子途径。最近的研究表明，表观遗传基因失活可能是肿瘤发生的第一步，可能是通过影响干细胞的正常分化以及使这些细胞易受其他致癌损伤。驱动癌前细胞表观遗传沉默的机制尚不清楚，但可能反映了对癌症前体细胞有益的简单随机事件。现在已经明确，表观遗传沉默的基因可以通过药物重新激活。一些DNA甲基转移酶抑制剂（5-氮杂胞苷和5-氮杂-2'-脱氧胞苷）或组蛋白脱乙酰酶抑制剂（伏立诺他）已被美国食品药品监督管理局批准用于临床，并且在其他地方已进入III期临床试验。表观遗传改变可能在更新和维持恶性克隆中起重要作用这一前景为表观遗传疗法在癌症预防和维持中的应用开辟了新的前景。
