Targeting aberrant chromatin structure in colorectal carcinomas
Targeting aberrant chromatin structure in colorectal carcinomas
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DOI：
10.1097/ppo.0b013e31803c72fe
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发表时间：
2007-01-01
期刊：
影响因子：
2.2
通讯作者：
Issa, Jean-Pierre J.
中科院分区：
文献类型：
--
作者：
Konishi, Kazuo;Issa, Jean-Pierre J.
DNA甲基化和组蛋白修饰等表观遗传过程现在被认为是调节哺乳动物细胞基因表达的关键事件，并且在不改变编码序列的情况下影响基因功能。肿瘤细胞通常表现出深刻的表观遗传学改变，通过改变关键基因的表达促进肿瘤发生。在结直肠肿瘤发生中，详细的分析导致了一个假设，即表观遗传变化在年龄相关的癌症易感性中起着关键作用，并单独鉴定了一种称为CpG岛甲基化酶表型的独特表型。CpG岛甲基化表型阳性结直肠癌与女性性别、年龄较大、近端位置、粘液组织学、KRAS和BRAF突变、野生型p53和微卫星不稳定性有显著相关性。影响染色质结构的组蛋白修饰也与肿瘤抑制基因失活密切相关，DNA甲基化和组蛋白修饰似乎形成了稳定基因沉默的强化网络。这一领域的许多兴奋点与染色质修饰药物逆转表观遗传变化的可能性有关。在CpG岛甲基化表型阳性的结直肠癌中，DNA甲基化抑制剂在体内恢复了关键的沉默途径（例如，错配修复缺陷），低甲基化可以在很大程度上消除小鼠模型中的肿瘤发生。抑制DNA甲基化和组蛋白去乙酰化的药物已在临床上使用，应在结直肠恶性肿瘤中进行测试。
Epigenetic processes such as DNA methylation and histone modifications are now recognized as critical events for regulation of gene expression in mammalian cells and affect gene function without a change in coding sequence. Neoplastic cells often show profound epigenetic alterations that contribute to tumorigenesis by altering expression of critical genes. In colorectal tumorigenesis, detailed analysis led to a hypothesis on a critical role for epigenetic changes in age-related cancer susceptibility and separately identified a distinct phenotype termed the CpG island methylater phenotype. CpG island methylator phenotype-positive colorectal cancers have significant associations with female sex, older age, proximal location, mucinous histology, KRAS and BRAF mutations, wild-type p53, and microsatellite instability. Histone modifications that affect chromatin structures are also closely implicated in tumor suppressor gene inactivation and DNA methylation and histone modifications seem to form reinforcing networks for stable gene silencing. Much of the excitement in this field relates to the possibility of therapeutic reversal of epigenetic changes by chromatin-modifying drugs. In CpG island methylator phenotype-positive colorectal cancers, DNA methylation inhibitors restore key silenced pathways in vivo (eg, mismatch repair defects), and hypomethylation can largely abolish tumorigenesis in a mouse model. Drugs that inhibit DNA methylation and histone deacetylation are in use in the clinic and should be tested in colorectal malignancy.