Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells.
Enhancer of zeste homolog 2 promotes the proliferation and invasion of epithelial ovarian cancer cells.
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DOI：
10.1158/1541-7786.mcr-10-0398
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Li H;Cai Q;Godwin AK;Zhang R
EZH2是多梳阻遏复合物2（PRC2）的催化亚基，其包括非催化亚基SUZ12和EED。当存在于PRC 2中时，EZH2催化组蛋白H3（H3K27Me3）的赖氨酸27残基上的三甲基化，导致基因表达的表观遗传沉默。在此，我们研究了EZH2在上皮性卵巢癌（EOC）中的表达和功能。当与原代人卵巢表面上皮（pHOSE）细胞相比时，EZH2、SUZ12和EED在测试的所有八种人EOC细胞系中以更高水平表达。一致地，与pHOSE细胞相比，H3K27Me3在人EOC细胞系中也过表达。与正常卵巢表面上皮（n=46）相比，EZH2在原代人EOC（n=134）中显著过表达（p<0.001）。EZH2表达与上皮性卵巢癌中Ki67（细胞增殖的标志物）的表达（p<0.001）和肿瘤分级（p=0.034）正相关，但与肿瘤分期（p=0.908）无关。在高级别浆液性组织型EOC患者（n=98）中，EZH2表达与总体（p=0.3）或无病生存期（p=0.2）无关。在异种移植模型中，EZH2表达的敲低降低了H3K27Me3的水平并抑制了体外和体内人EOC细胞的生长。EZH2敲低诱导人EOC细胞凋亡。最后，我们发现EZH2敲低抑制了人EOC细胞的侵袭。总之，这些数据表明EZH2在人EOC细胞中经常过表达，并且其过表达促进人EOC细胞的增殖和侵袭，表明EZH2是开发EOC治疗剂的潜在靶标。
EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that includes non-catalytic subunits SUZ12 and EED. When present in PRC2, EZH2 catalyzes trimethylation on lysine 27 residue of histone H3 (H3K27Me3), resulting in epigenetic silencing of gene expression. Here, we investigated the expression and function of EZH2 in epithelial ovarian cancer (EOC). When compared to primary human ovarian surface epithelial (pHOSE) cells, EZH2, SUZ12 and EED were expressed at higher levels in all eight human EOC cell lines tested. Consistently, H3K27Me3 was also overexpressed in human EOC cell lines compared to pHOSE cells. EZH2 was significantly overexpressed in primary human EOCs (n=134) when compared to normal ovarian surface epithelium (n=46) (p<0.001). EZH2 expression positively correlated with expression of Ki67 (p<0.001) (a marker of cell proliferation) and tumor grade (p=0.034) but not tumor stage (p=0.908) in EOC. There was no correlation of EZH2 expression with overall (p=0.3) or disease-free survival (p=0.2) in high-grade serous histotype EOC patients (n=98). Knockdown of EZH2 expression reduced the level of H3K27Me3 and suppressed the growth of human EOC cells both in vitro and in vivo in xenograft models. EZH2 knockdown induced apoptosis of human EOC cells. Finally, we showed that EZH2 knockdown suppressed the invasion of human EOC cells. Together, these data demonstrate that EZH2 is frequently overexpressed in human EOC cells and its overexpression promotes the proliferation and invasion of human EOC cells, suggesting that EZH2 is a potential target for developing EOC therapeutics.