Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2.
Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2.
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DOI：
10.1158/1078-0432.ccr-08-1013
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Billadeau DD
中科院分区：
文献类型：
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作者：
Ougolkov AV;Bilim VN;Billadeau DD
zeste 同源物增强子 2 (EZH2) 是一种组蛋白甲基转移酶，通过染色质重塑在转录抑制中发挥关键作用。我们的目的是确定 EZH2 的表达模式并评估 EZH2 缺失在胰腺癌细胞中的抗癌作用。进行免疫组织化学和胞质/核分级分离以确定 EZH2 在正常胰腺和人胰腺肿瘤中的表达模式。我们使用 RNA 干扰、蛋白质印迹、RT-PCR 和染色质免疫沉淀来研究 EZH2 缺失对胰腺癌细胞增殖和存活的影响。我们在胰腺癌细胞系和 104 例人类胰腺癌病例中的 71 例 (68%) 中检测到 EZH2 的核过度表达。 EZH2 核积聚在低分化胰腺腺癌中更为频繁（34 例中有 31 例，p<0.001）。我们发现 EZH2 的基因缺失会导致 p27Kip1 的重新表达并减少胰腺癌细胞的增殖。此外，我们发现，EZH2 缺失使胰腺癌细胞对阿霉素和吉西他滨敏感，从而显着诱导细胞凋亡，这表明 EZH2 抑制剂与标准化疗的组合可能是胰腺癌的一种优越的潜在治疗方法。我们的结果证明EZH2的核积累是低分化胰腺腺癌的一个标志，确定抑癌基因p27Kip1作为EZH2的新靶基因，表明EZH2核过度表达有助于胰腺癌细胞增殖，并表明EZH2作为治疗胰腺癌的潜在治疗靶点。
Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objective was to determine the expression pattern of EZH2 and assess the anticancer effect of EZH2 depletion in pancreatic cancer cells. Immunohistochemistry and cytosolic/nuclear fractionation were performed to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, RT-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival. We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (in 31 of 34 cases, p<0.001). We found that genetic depletion of EZH2 results in re-expression of p27Kip1 and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine leading to a significant induction of apoptosis suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer. Our results demonstrate nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma, identify the tumor suppressor p27Kip1 as a new target gene of EZH2, show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation, and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.