DZNep介导EZH2调控CDH13甲基化抗卵巢癌的作用机制及靶向治疗的研究

Recently, there have been intensive studies concerning the epigenetic target therapy. It was reported that 3-Deazaneplanocin A (DZNep) treatment of cancer cells inhibits enhancer of zeste homolog 2 (EZH2) activity, blocks proliferation and induces apoptosis in some malignant tumors. However, the effect of DZNep upon ovarian cancer is currently unclear, and the underlying molecular mechanisms are not well understood, especially, little is known about speci?c genetic determinants regulating tumor responses to DZNep. Our previous study demonstrates that DZNep depletes EZH2 and induces apoptosis in ovarian cancer cells. In addition, we found that EZH2 regulates the methylation levels of CDH13 promoter. We suspected that DZNep reduces proliferation and invasiveness in ovarian cancer possibly through inhibiting EZH2 function and down-regulating the methylation levels of CDH13 promoter. Our study aimed to investigate the mechanism that DZNep mediates EZH2, inhibits CDH13 methylation and suppresses tumor growth in ovarian cancer, demonstrate that CDH13 may be a potential biomarker for DZNep based EZH2-targeting epigenetic therapy.

近年来表观遗传分子靶向治疗成为研究热点。实验证明新出现的组蛋白甲基转移酶抑制剂DZNep在某些恶性肿瘤中能干扰组蛋白甲基转移酶EZH2的活性,抑制肿瘤增殖和诱导凋亡。然而，DZNep在卵巢癌中的作用却鲜有报道，且DZNep的作用机制迄今不明，尤其是缺少预测其疗效的生物标记。我们的前期研究显示DZNep能促进卵巢癌细胞凋亡且抑制致癌基因EZH2的表达，同时发现EZH2对抑癌基因CDH13的甲基化状态有调控作用。因此，我们设想DZNep 是通过抑制EZH2活性，降低CDH13基因的高甲基化水平，恢复CDH13的表达，从而抑制卵巢癌细胞的增殖和侵袭。本项目将首次从组织、细胞和动物水平验证DZNep对卵巢癌的抑制作用，阐明DZNep介导EZH2调控CDH13甲基化抑制肿瘤生长的机制，证明CDH13可能作为DZNep介导的EZH2靶向治疗中预测疗效的指标，为临床实现基因导向性个体化治疗提供实验基础。

近年来表观遗传分子靶向治疗成为研究热点。实验证明新出现的组蛋白甲基转移酶抑制剂DZNep在某些恶性肿瘤中能干扰组蛋白甲基转移酶EZH2的活性,抑制肿瘤增殖和诱导凋亡。然而，DZNep 在卵巢癌中的作用却鲜有报道，且 DZNep 的作用机制迄今不明，尤其是缺少预测其疗效的生物标记。我们的研究发现，DZNep可抑制卵巢癌细胞的增殖、侵袭并促进细胞晚期凋亡。同时，我们在动物模型水平验证了DZNep对卵巢癌的抑制作用和安全性。我们发现，在卵巢癌组织中，EZH2和CDH13的蛋白表达呈负相关，且与卵巢癌的临床特征相关。DZNep可降低EZH2的表达，同时对CDH13基因的表达有调控作用。提出CDH13 可能作为 DZNep 介导的 EZH2 靶向治疗中预测疗效的指标，为临床实现基因导向性个体化治疗提供实验基础。