Global Levels of Histone Modifications Predict Prostate Cancer Recurrence
Global Levels of Histone Modifications Predict Prostate Cancer Recurrence
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DOI：
10.1002/pros.21038
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发表时间：
2010-01-01
期刊：
影响因子：
2.8
通讯作者：
von Ruecker, Alexander
中科院分区：
文献类型：
--
作者：
Ellinger, Joerg;Kahl, Philip;von Ruecker, Alexander
目的.表观遗传学改变如DNA甲基化和组蛋白修饰在肿瘤发生中起重要作用。据报道，整体组蛋白修饰模式是各种肿瘤实体中癌症复发的预测因子。我们的研究是为了评估组蛋白赖氨酸（H（x）K（y））和组蛋白乙酰基（H（x）Ac）修饰在前列腺组织。用针对H3 K4单-（H3 K4 mel）、二-（H3 K4 me 2）、三-（H3 K4 me 3）甲基化、H3 K9 mel、H3 K9 me 2、H3 K9 me 3、H3和H4全乙酰化（H3 Ac、H4 Ac）的抗体对具有113个前列腺癌（PCA）、23个非恶性前列腺组织的组织微阵列进行染色。我们还分析了晚期PCA患者（难治性PCA-HRPC，n = 34;依赖性PCA，n = 30）的H3 K4甲基化。根据染色强度和显示核染色的上皮细胞比例对切片进行评分。与非恶性前列腺组织相比，H3 K4 mel、H3 K9 me 2、H3 K9 me 3、H3 Ac和H4 Ac在PCA中显著降低。H3 Ac和H3 K9 me 2水平允许PCA和非恶性前列腺组织的高度特异性（> 91%）和敏感性（> 78%）的区分，如通过ROC分析（AUC > 0.91）确定的。组蛋白赖氨酸甲基化和组蛋白乙酰化标记与临床病理参数相关（即，直肠指检、术前PSA、pT分期、淋巴结转移、Gleason评分）。此外，H3 K4 mel是根治性前列腺切除术后PSA复发的重要预测因子。HRPC中H3 K4 mel、H3 K4 me 2和H3 K4 me 3水平显著升高。整体组蛋白修饰水平可能有助于识别预后不良的患者，并代表未来PCA治疗的目标。前列腺70：61-69，2010年。(c)2009 Wiley-Liss，Inc.
PURPOSE. Epigenetic alterations such as DNA methylation and histone modifications play important roles in carcinogenesis. It was reported that global histone modification patterns are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone lysine (H(x)K(y)) and histone acetyl (H(x)Ac) modifications in prostate tissue.MATERIALS AND METHODS. A tissue microarray with 113 prostate cancer (PCA), 23 non-malignant prostate tissues was stained with antibodies against H3K4 mono-(H3K4mel), di-(H3K4me2), tri-(H3K4me3) methylation, H3K9mel, H3K9me2, H3K9me3, H3 and H4 panacetylation (H3Ac, H4Ac). We also analyzed H3K4 methylation in patients with advanced PCA (hormone-refractory PCA-HRPC, n = 34; hormone-dependent PCA, n = 30). Sections were scored according the staining intensity and the proportion of epithelial cells showing nuclear staining.RESULTS. H3K4mel, H3K9me2, H3K9me3, H3Ac, and H4Ac were significantly reduced in PCA compared to non-malignant prostate tissue. H3Ac and H3K9me2 levels allowed discrimination of PCA and non-malignant prostate tissue highly specifically (> 91%) and sensitively (> 78%) as determined via ROC analyses (AUC > 0.91). Histone lysine methylation and histone acetylation marks were correlated with clinical-pathological parameters (i.e., digital rectal examination, preoperative PSA, pT-stage, lymph node metastasis, Gleason score). In addition, H3K4mel was a significant predictor of PSA recurrence following radical prostatectomy. H3K4mel, H3K4me2, and H3K4me3 levels were significantly increased in HRPC.CONCLUSIONS. Global histone modification levels may help to identify patients with adverse prognosis, and represent a target for the future therapy of PCA. Prostate 70: 61-69, 2010. (c) 2009 Wiley-Liss, Inc.