Li Zhongwu, Wang Yanling, Qiu Jing, Li Qiang, Yuan Chunping, Zhang Wei, Wang Dongmiao, Ye Jinhai, Jiang Hongbin, Yang Jianrong, Cheng Jie
Head Neck Cancer Center, Institute of Stomatology, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China PRC.
Oncotarget. 2013 Dec;4(12):2532-49. doi: 10.18632/oncotarget.1503.
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.
EZH2是多梳抑制复合物2（PRC2）的核心成员，通过催化组蛋白3赖氨酸27（H3K27）的三甲基化介导转录沉默，这在癌症的发生和发展中起关键作用。在此，我们通过使用小干扰RNA和EZH2抑制剂DZNep的功能丧失试验，研究了EZH2在舌癌发生中的表达模式和生物学作用。我们还确定了DZNep在体内对舌癌的治疗效果。我们发现，EZH2在舌癌中异常过表达与病理分级、颈部淋巴结转移和Ki-67表达相关。EZH2升高与总生存期缩短相关，并且在舌癌患者中显示出显著且独立的预后重要性。EZH2的基因敲除和药物抑制均抑制细胞增殖、迁移、侵袭和集落形成，并可能部分通过调节p16、p21和E-钙黏蛋白减少CD44+亚群。此外，DZNep增强了5-氟尿嘧啶的抗癌作用。此外，腹腔注射DZNep诱导的肿瘤内EZH2抑制在舌癌异种移植模型中显著减弱了肿瘤生长。综上所述，我们的结果表明，EZH2在舌癌发生过程中作为具有多种致癌功能的关键驱动因子，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EZH2的治疗干预开辟了可能性。
