EZH2 Represses Target Genes through H3K27-Dependent and H3K27-Independent Mechanisms in Hepatocellular Carcinoma
EZH2 Represses Target Genes through H3K27-Dependent and H3K27-Independent Mechanisms in Hepatocellular Carcinoma
复制标题
EZH2 在肝细胞癌中通过 H3K27 依赖性和 H3K27 独立机制抑制靶基因。
DOI：
10.1158/1541-7786.mcr-14-0034
复制
发表时间：
2014-10-01
影响因子：
5.2
通讯作者：
Jin, Guang-Hui
中科院分区：
文献类型：
--
作者：
Gao, Shu-Bin;Zheng, Qi-Fan;Jin, Guang-Hui
多梳组（polycomb group，PcG）基因的改变直接调节组蛋白H3赖氨酸27（H3K27me3）的三甲基化，从而可能影响肝细胞癌（HCC）的表观基因组，这对控制HCC细胞表型至关重要。然而，PcGs在HCC中的下游调节程度还没有很好的定义。使用cDNA微阵列分析，我们发现，PcGs的靶基因网络包含完善的基因，如细胞周期蛋白依赖性激酶抑制剂（CDKN2A），和以前未描述的PcG调控的基因，包括E2F1，NOTCH2和TP53。使用染色质免疫沉淀分析，我们证明了EZH2占用与H3K27me3在E2F1和NOTCH 2启动子处一致。有趣的是，PcG抑制人肝癌细胞中典型的肿瘤抑制因子TP53的表达，并且在某些肝癌标本中，PcG水平的升高与TP53的下调相关。出乎意料的是，我们在TP53启动子处没有发现明显的H3K27me3修饰或EZH2结合信号，表明PcG以H3K27me3非依赖性方式调节TP53表达。最后，PcGs表达的降低有效地阻断了体外和体内肝癌细胞的侵袭性特征。（C）2014年AACR。
Alterations of polycomb group (PcG) genes directly modulate the trimethylation of histone H3 lysine 27 (H3K27me3) and may thus affect the epigenome of hepatocellular carcinoma (HCC), which is crucial for controlling the HCC cell phenotype. However, the extent of downstream regulation by PcGs in HCC is not well defined. Using cDNA microarray analysis, we found that the target gene network of PcGs contains well-established genes, such as cyclin-dependent kinase inhibitors (CDKN2A), and genes that were previously undescribed for their regulation by PcG, including E2F1, NOTCH2, and TP53. Using chromatin immunoprecipitation assays, we demonstrated that EZH2 occupancy coincides with H3K27me3 at E2F1 and NOTCH2 promoters. Interestingly, PcG repress the expression of the typical tumor suppressor TP53 in human HCC cells, and an increased level of PcG was correlated with the downregulation of TP53 in certain HCC specimens. Unexpectedly, we did not find obvious H3K27me3 modification or an EZH2 binding signal at the TP53 promoters, suggesting that PcG regulates TP53 expression in an H3K27me3-independent manner. Finally, the reduced expression of PcGs effectively blocked the aggressive signature of liver cancer cells in vitro and in vivo. (C)2014 AACR.