Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer.
Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer.
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发表时间：
2003-11
期刊：
影响因子：
11.2
通讯作者：
S. Belinsky;D. Klinge;C. Stidley;J. Issa;J. Herman;T. March;S. Baylin
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作者：
S. Belinsky;D. Klinge;C. Stidley;J. Issa;J. Herman;T. March;S. Baylin
在肿瘤抑制基因中具有种系突变的小鼠中，胞嘧啶-DNA甲基转移酶1（DNMT 1）基因的一个等位基因的破坏先前被证明可以减少幼年动物的肿瘤形成。这种效应现在在我们对成熟小鼠的研究中重现，其中这种遗传性DNMT 1减少导致烟草致癌物诱导的肺癌减少50%，并且引起肿瘤的II型肺细胞中DNMT活性类似减少。用低剂量的去甲基化剂5-氮杂-2 '-脱氧胞苷短期治疗DNMT野生型雌性小鼠，肿瘤的发生率降低了30%。重要的是，当5-氮杂-2 '-脱氧胞苷与组蛋白去乙酰化酶抑制剂苯丁酸钠组合时，肺肿瘤发展显著减少>50%;单独使用苯丁酸钠没有观察到效果。这种相同的抑制剂组合也协同作用，导致人类癌细胞中高度甲基化和转录沉默的肿瘤抑制基因的再表达。因此，DNMT和组蛋白脱乙酰酶活性的降低可能会阻止表观遗传介导的基因沉默，这可能会提供一种新的临床策略，以帮助预防美国癌症死亡的主要原因。
Disruption of one allele for the cytosine-DNA methyltransferase 1 (DNMT1) gene in mice with a germ-line mutation in a tumor suppressor gene was shown previously to reduce tumor formation in juvenile animals. This effect is now reproduced in our studies of mature mice where this genetic DNMT1 reduction leads to a 50% decrease in tobacco carcinogen-induced lung cancer and a similar reduction in DNMT activity in type II pneumocytes that give rise to the tumors. Short-term treatment of DNMT wild-type female mice with low doses of the demethylating agent 5-aza-2'-deoxycytidine decreased the incidence of neoplasms by 30%. Importantly, when 5-aza-2'-deoxycytidine was combined with the histone deacetylase inhibitor sodium phenylbutyrate, lung tumor development was significantly reduced by >50%; no effect was seen with phenylbutyrate alone. This identical combination of inhibitors also acts synergistically to cause re-expression of densely hypermethylated and transcriptionally silenced tumor suppressor genes in human cancer cells. Thus, reduction in DNMT and histone deacetylase activities that likely block epigenetically mediated gene silencing might provide a novel clinical strategy to help prevent the leading cause of cancer death in the United States.