The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma
The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma
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EZH2 和 menin 在肝细胞癌中的功能和机制相关性。
DOI：
10.1016/j.jhep.2014.05.015
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发表时间：
2014-10-01
影响因子：
25.7
通讯作者：
Jin, Guang-Hui
中科院分区：
文献类型：
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作者：
Gao, Shu-Bin;Xu, Bin;Jin, Guang-Hui
背景尺寸目标：组蛋白修饰的改变可能作为肝细胞癌（HCC）的一个有前途的诊断生物标志物，但组蛋白H3赖氨酸27和4三甲基化（H3 K27 me 3和H3 K4 me 3）在HCC中的临床和机制相关性仍然知之甚少。在这里，我们建议，H3 K27 me 3和H3 K4 me 3的组合是一个更精确的预测/预后价值HCC patients.Methods：我们使用染色质免疫沉淀（ChIP）测定和ChIP-on-chip屏幕分析HCC.结果：我们发现，EZH 2占用与H3 K27 me 3在启动子和直接沉默的靶基因在HCC中的转录。EZH 2的H3 K27 me 3相关基因网络包含成熟的基因，如CDKN 2A，以及以前未被识别的基因，包括FOXO 3，E2 F1和NOTCH 2等。我们进一步观察到HCC标本中某些靶基因启动子处H3 K27 me 3和H3 K4 me 3的独立增加谱。重要的是，Kaplan-Meier分析显示，与EZH 2或menin表达不足的患者相比，同时表达EZH 2和menin的患者的3年总体和无肿瘤生存率显著降低。此外，H3 K27 me 3的抑制剂单独或与H3 K4 me 3抑制剂组合，有效地阻断了HCC细胞的侵袭性表型。结论：我们的研究结果表明，H3 K27 me 3和H3 K4 me 3的联合分析可以作为HCC的强有力的诊断生物标志物，靶向两者可能有利于抗HCC治疗。(C)2014年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background Sz Aims: The alterations of histone modification may serve as a promising diagnostic biomarker of hepatocellular carcinoma (HCC), but the clinical and mechanistic relatedness of the histone H3 lysine 27 and 4 trimethylation (H3K27me3 and H3K4me3) in HCC remains poorly understood. Here we propose that the combination of H3K27me3 and H3K4me3 is a more precise predictive/prognostic value for outcome of HCC patients.Methods: We used chromatin immunoprecipitation (ChIP) assays and a ChIP-on-chip screen to analyse HCC.Results: We found that the EZH2 occupancy coincides with the H3K27me3 at promoters and directly silences the transcription of target genes in HCC. The H3K27me3-related gene network of EZH2 contains well-established genes, such as CDKN2A, as well as previously unappreciated genes, including FOXO3, E2F1, and NOTCH2, among others. We further observed independently increasing profiles of H3K27me3 and H3K4me3 at the promoters of certain target genes in HCC specimens. Importantly, Kaplan-Meier analysis reveals that 3-year overall and tumour-free survival rates are dramatically reduced in patients that simultaneously express EZH2 and menin, compared to rates in the EZH2 or menin under expressing patients. Furthermore, an inhibitor of H3K27me3 alone, or in combination with an H3K4me3 inhibitor, effectively blocked the aggressive phenotype of HCC cells.Conclusions: Our results indicate that a combined analysis of both H3K27me3 and H3K4me3 may serve as powerful diagnostic biomarkers of HCC, and targeting both might benefit anti-HCC therapy. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.