The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer.
The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer.
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多梳蛋白EZH2是舌癌的新治疗靶点
DOI：
10.18632/oncotarget.1503
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Cheng J
中科院分区：
文献类型：
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作者：
Li Z;Wang Y;Qiu J;Li Q;Yuan C;Zhang W;Wang D;Ye J;Jiang H;Yang J;Cheng J
EZH 2是多梳阻遏复合物2（PRC 2）的核心成员，通过催化组蛋白3赖氨酸27（H3 K27）的三甲基化来介导转录沉默，其在癌症的起始和进展中起关键作用。在这里，我们研究了EZH 2的表达模式和生物学作用，在舌肿瘤发生的功能丧失试验，使用小干扰RNA和EZH 2抑制剂DZNep。我们还确定了DZNep对体内舌癌的治疗效率。我们发现EZH 2的异常过表达与舌癌的病理分级、颈淋巴结转移和Ki-67的表达有关。升高的EZH 2与较短的总生存期相关，并在舌癌患者中显示出显著和独立的预后重要性。EZH 2的基因和药理学缺失均抑制细胞增殖、迁移、侵袭和集落形成，并可能部分通过调节p16、p21和E-caherin来降低CD 44+亚群。此外，DZNep增强了5-氟尿嘧啶的抗癌作用。此外，在舌癌异种移植模型中，由DZNep腹膜内施用诱导的肿瘤内EZH 2抑制显著减弱肿瘤生长。综上所述，我们的研究结果表明，EZH 2是舌肿瘤发生过程中具有多种致癌功能的关键驱动因素，也是舌癌诊断和预后预测的新生物标志物。这些发现为舌癌中针对EZH 2的治疗性干预开辟了可能性。
EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.