SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK.
SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK.
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DOI：
10.1158/1541-7786.mcr-12-0335
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Zhang R
中科院分区：
文献类型：
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作者：
Li H;Cai Q;Wu H;Vathipadiekal V;Dobbin ZC;Li T;Hua X;Landen CN;Birrer MJ;Sánchez-Beato M;Zhang R
上皮性卵巢癌（EOC）在美国妇科癌症死亡原因中排名第一。SUZ12是多梳抑制复合体2 （PRC2）的一个组成部分，通过在组蛋白H3的赖氨酸27残基（H3K27Me3）上产生三甲基化，对PRC2介导的基因沉默至关重要。SUZ12在EOC中的作用从未被研究过。在这里，我们发现SUZ12在人EOC （n=117）中的表达水平显著高于正常人卵巢表面上皮（n=35, p<0.001）或输卵管上皮（n=15, p<0.001）。SUZ12与EZH2在人EOC中的表达呈正相关（p<0.001）。此外，SUZ12的表达与细胞增殖标志物Ki67呈正相关（p<0.001），并预测较短的总生存期（p=0.0078）。值得注意的是，在原位和皮下异种移植EOC模型中，敲低SUZ12可抑制人EOC细胞的体外和体内生长。此外，SUZ12敲低可降低H3K27Me3水平，触发人EOC细胞凋亡。在机制上，我们确定了促凋亡基因HRK作为SUZ12的新靶基因，并证明了HRK上调介导SUZ12敲低诱导的人EOC细胞凋亡。综上所述，我们发现SUZ12通过抑制凋亡促进人EOC细胞的增殖，而HRK是SUZ12的一个新的靶基因，其上调有助于SUZ12敲低诱导细胞凋亡。
Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here we show that SUZ12 is expressed at significantly higher levels in human EOC (n=117) compared with either normal human ovarian surface epithelium (n=35, p<0.001) or fallopian tube epithelium (n=15, p<0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (p<0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (p<0.001), and predicts shorter overall survival (p=0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified HRK, a pro-apoptotic gene, as a novel SUZ12 target gene, and demonstrated that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown.