A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition
A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition
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DOI：
10.1038/ng1773
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发表时间：
2006-05-01
期刊：
影响因子：
30.8
通讯作者：
Esteller, M
中科院分区：
文献类型：
--
作者：
Ropero, S;Fraga, MF;Esteller, M
组蛋白乙酰化模式的破坏是癌细胞的共同特征，但对其遗传基础知之甚少。我们已经在具有微卫星不稳定性的散发性癌和遗传性非息肉病性结直肠癌综合征个体中发现了一种主要的人类组蛋白去乙酰化酶HDAC2的截短突变。HDAC2移码突变的存在导致HDAC2蛋白表达和酶活性的丧失，并使这些细胞对组蛋白去乙酰化酶抑制剂通常的抗增殖和促凋亡作用更具抵抗力。由于这些药物可以作为癌症的治疗药物，我们的研究结果支持在未来这些个体的药物遗传学治疗中使用HDAC2突变状态。
Disruption of histone acetylation patterns is a common feature of cancer cells, but very little is known about its genetic basis. We have identified truncating mutations in one of the primary human histone deacetylases, HDAC2, in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. The presence of the HDAC2 frameshift mutation causes a loss of HDAC2 protein expression and enzymatic activity and renders these cells more resistant to the usual antiproliferative and proapoptotic effects of histone deacetylase inhibitors. As such drugs may serve as therapeutic agents for cancer, our findings support the use of HDAC2 mutational status in future pharmacogenetic treatment of these individuals.