Momparler Richard L
Département de pharmacology, Université de Montréal, Centre de recherché, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine Montreal, Que H3T 1C5, Canada.
Oncogene. 2003 Sep 29;22(42):6479-83. doi: 10.1038/sj.onc.1206774.
Aberrant DNA methylation of the promoter region is a key mechanism for inactivation of genes that suppress tumorigenesis. Genes that are involved in every step of tumor formation can be silenced by this mechanism. Inhibitors of DNA methylation, such as 5-azadeoxycytidine (5AZA), can reverse this epigenetic event suggesting a potential use in cancer therapy. The structure of chromatin can also play an important role with respect to the regulation of gene expression. Chromatin containing hypoacetylated lysines in histones has a compact structure that is repressive for transcription. Inhibitors of histone deacetylase (HDAC) can convert chromatin to an open structure and activate certain genes that inhibit tumor growth. These HDAC inhibitors also have potential in cancer therapy. A 'cross-talk' between DNA methylation and histone deacetylation can occur and work in concert to silence gene expression. The molecular mechanism involves the attachment of a methylated CpG binding protein (MBP) to the methylated promoters and its recruitment of HDAC to form a complex that suppresses transcription. These two epigenetic modifications represent an interesting target for therapeutic intervention using 5AZA and HDAC inhibitors. These agents in combination have been shown to produce a synergistic reactivation of tumor suppressor genes and an enhanced antineoplastic effect against tumor cells, and should be investigated as a novel form of epigenetic therapy for cancer.
启动子区域异常的DNA甲基化是导致抑制肿瘤发生的基因失活的关键机制。参与肿瘤形成各个步骤的基因都可通过这一机制沉默。DNA甲基化抑制剂，如5-氮杂脱氧胞苷（5AZA），可逆转这种表观遗传事件，提示其在癌症治疗中的潜在用途。染色质结构在基因表达调控方面也可发挥重要作用。组蛋白中含有低乙酰化赖氨酸的染色质具有紧密结构，对转录具有抑制作用。组蛋白脱乙酰酶（HDAC）抑制剂可使染色质转变为开放结构，并激活某些抑制肿瘤生长的基因。这些HDAC抑制剂在癌症治疗中也具有潜力。DNA甲基化与组蛋白去乙酰化之间可发生“串扰”，协同作用使基因表达沉默。分子机制涉及甲基化CpG结合蛋白（MBP）附着于甲基化启动子，并募集HDAC形成抑制转录的复合物。这两种表观遗传修饰是使用5AZA和HDAC抑制剂进行治疗干预的一个有趣靶点。已证明这些药物联合使用可产生协同作用，重新激活肿瘤抑制基因，并增强对肿瘤细胞的抗肿瘤作用，应作为一种新型癌症表观遗传疗法进行研究。
