Global histone modification patterns predict risk of prostate cancer recurrence
Global histone modification patterns predict risk of prostate cancer recurrence
复制标题
DOI：
10.1038/nature03672
复制
发表时间：
2005-06-30
期刊：
影响因子：
64.8
通讯作者：
Kurdistani, SK
中科院分区：
文献类型：
--
作者：
Seligson, DB;Horvath, S;Kurdistani, SK
组蛋白翻译后修饰中的异常已被证明发生在癌细胞中，但仅发生在单个启动子中(1)；它们与临床结果无关。除了针对启动子，组蛋白的修饰，如赖氨酸和精氨酸残基的乙酰化和甲基化，也发生在染色质的大区域，包括编码区和非启动子序列，这被称为全局组蛋白修饰(2)。在这里，我们展示了个体组蛋白修饰的全球水平的变化也与癌症相关，并且这些变化可以预测临床结果。通过原发前列腺切除组织标本的免疫组织化学染色，确定组蛋白H3和H4中5个残基的组蛋白乙酰化和二甲基化染色的细胞百分比。对具有相似修饰模式的样本进行分组，发现在低级别前列腺癌患者中，两种疾病亚型具有不同的肿瘤复发风险。这些组蛋白修饰模式是独立于肿瘤分期、术前前列腺特异性抗原水平和包膜侵犯的预后预测因子。因此，特异性组蛋白修饰的广泛变化表明前列腺癌中以前未描述的分子异质性，并可能是癌症患者广泛的临床行为的基础。
Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters(1); they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications(2). Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.