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TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2021-06-26 , DOI: 10.1038/s41418-021-00824-w
Tao Gui 1, 2 , Ming Liu 1 , Bing Yao 1, 3 , Haiqin Jiang 1 , Dongjun Yang 1 , Qixiang Li 1 , Xiangwei Zeng 1 , Ying Wang 1 , Jian Cao 4 , Yexuan Deng 1 , Xinyu Li 1 , Peipei Xu 1 , Liqin Zhou 5 , Dake Li 4 , Zhihui Wang 5 , Ke Zen 1 , David C S Huang 6 , Bing Chen 1 , Guiping Wan 2 , Quan Zhao 1
Affiliation  

Endometrial cancer (EC) is the most common gynecological malignancy worldwide. However, the molecular mechanisms underlying EC progression are still largely unknown, and chemotherapeutic options for EC patients are currently very limited. In this study, we found that histone methyltransferase EZH2 and DNA methyltransferase DNMT3B were upregulated in EC samples from patients, and promoted EC cell proliferation as evidenced by assays of cell viability, cell cycle, colony formation. Mechanistically, we found that EZH2 promoted EC cell proliferation by epigenetically repressing TCF3, a direct transcriptional activator of CCKN1A (p21WAF1/Cip1), in vitro and in vivo. In addition, we found that DNMT3B specifically methylated the TCF3 promoter, repressing TCF3 expression and accelerating EC cell proliferation independently of EZH2. Importantly, elevated expression of EZH2 or DNMT3B in EC patients inversely correlated with expression of TCF3 and p21, and was associated with shorter overall survival. We show that combined treatment with GSK126 and 5-Aza-2d treatment wit synergistically inhibited methyltransferase activity of EZH2 and DNMT3B, resulting in a profound block of EC cell proliferation as well as EC tumor progression in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. These findings reveal that TCF3 functions as a tumor suppressor epigenetically silenced by EZH2 and DNMT3B in EC, and support the notion that targeting the EZH2/DNMT3B/TCF3/p21 axis may be a novel and effective therapeutic strategy for treatment of EC.



中文翻译:


TCF3 被 EZH2 和 DNMT3B 表观遗传沉默,并在子宫内膜癌中发挥肿瘤抑制因子的作用



子宫内膜癌(EC)是全世界最常见的妇科恶性肿瘤。然而,EC进展的分子机制仍然很大程度上未知,并且EC患者的化疗选择目前非常有限。在这项研究中,我们发现患者 EC 样本中组蛋白甲基转移酶 EZH2 和 DNA 甲基转移酶 DNMT3B 表达上调,并通过细胞活力、细胞周期、集落形成测定证明促进 EC 细胞增殖。从机制上讲,我们发现 EZH2 在体外和体内通过表观遗传抑制 TCF3(CCKN1A (p21 WAF1/Cip1 ) 的直接转录激活因子)来促进 EC 细胞增殖。此外,我们发现DNMT3B特异性甲基化TCF3启动子,抑制TCF3表达并独立于EZH2加速EC细胞增殖。重要的是,EC患者中EZH2或DNMT3B的表达升高与TCF3和p21的表达呈负相关,并且与较短的总生存期相关。我们发现,GSK126 和 5-Aza-2d 联合治疗可协同抑制 EZH2 和 DNMT3B 的甲基转移酶活性,从而显着阻断细胞系来源的异种移植物 (CDX) 和患者的 EC 细胞增殖以及 EC 肿瘤进展-衍生的异种移植(PDX)小鼠模型。这些研究结果表明,TCF3 在 EC 中发挥表观遗传学沉默作用,被 EZH2 和 DNMT3B 沉默,并支持这样的观点:靶向 EZH2/DNMT3B/TCF3/p21 轴可能是治疗 EC 的一种新颖且有效的治疗策略。

更新日期:2021-06-28
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