TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer.
TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer.
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TCF3 被 EZH2 和 DNMT3B 表观遗传沉默，并在子宫内膜癌中充当肿瘤抑制因子。
DOI：
10.1038/s41418-021-00824-w
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发表时间：
2021-12
影响因子：
12.4
通讯作者：
Zhao Q
中科院分区：
文献类型：
--
作者：
Gui T;Liu M;Yao B;Jiang H;Yang D;Li Q;Zeng X;Wang Y;Cao J;Deng Y;Li X;Xu P;Zhou L;Li D;Wang Z;Zen K;Huang DCS;Chen B;Wan G;Zhao Q
子宫内膜癌是世界范围内最常见的妇科恶性肿瘤。然而，EC进展的分子机制在很大程度上仍然未知，EC患者的化疗选择目前非常有限。在本研究中，我们发现组蛋白甲基转移酶EZH2和DNA甲基转移酶DNMT3B在患者EC样本中上调，并通过细胞活力、细胞周期和集落形成的实验证明了其促进EC细胞增殖的作用。在体外和体内实验中，我们发现EZH2通过表观遗传抑制CCKN1A （p21WAF1/Cip1）的直接转录激活因子TCF3促进EC细胞增殖。此外，我们发现DNMT3B特异性甲基化TCF3启动子，独立于EZH2抑制TCF3表达并加速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，从而在细胞系来源的异种移植（CDX）和患者来源的异种移植（PDX）小鼠模型中显著阻断EC细胞增殖和EC肿瘤进展。这些发现表明，TCF3在EC中作为一种被EZH2和DNMT3B表观遗传沉默的肿瘤抑制因子，并支持靶向EZH2/DNMT3B/TCF3/p21轴可能是治疗EC的一种新的有效治疗策略。
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.
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DOI：
10.1016/j.bbrc.2012.04.126
发表时间：
2012-05-25
影响因子：
3.1
作者：
Patel D;Chaudhary J
通讯作者：
Chaudhary J
NatD 通过阻止组蛋白 H4 丝氨酸磷酸化激活 Slug 表达来促进肺癌进展
影响因子：
16.6
作者：
Ju J;Chen A;Deng Y;Liu M;Wang Y;Wang Y;Nie M;Wang C;Ding H;Yao B;Gui T;Li X;Xu Z;Ma C;Song Y;Kvansakul M;Zen K;Zhang CY;Luo C;Fang M;Huang DCS;Allis CD;Tan R;Zeng CK;Wei J;Zhao Q
通讯作者：
Zhao Q
DOI：
10.1097/igc.0b013e318296a265
发表时间：
2013-07
期刊：
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
影响因子：
--
作者：
Eskander RN;Ji T;Huynh B;Wardeh R;Randall LM;Hoang B
通讯作者：
Hoang B
影响因子：
30.8
作者：
Fischer U;Forster M;Rinaldi A;Risch T;Sungalee S;Warnatz HJ;Bornhauser B;Gombert M;Kratsch C;Stütz AM;Sultan M;Tchinda J;Worth CL;Amstislavskiy V;Badarinarayan N;Baruchel A;Bartram T;Basso G;Canpolat C;Cario G;Cavé H;Dakaj D;Delorenzi M;Dobay MP;Eckert C;Ellinghaus E;Eugster S;Frismantas V;Ginzel S;Haas OA;Heidenreich O;Hemmrich-Stanisak G;Hezaveh K;Höll JI;Hornhardt S;Husemann P;Kachroo P;Kratz CP;Te Kronnie G;Marovca B;Niggli F;McHardy AC;Moorman AV;Panzer-Grümayer R;Petersen BS;Raeder B;Ralser M;Rosenstiel P;Schäfer D;Schrappe M;Schreiber S;Schütte M;Stade B;Thiele R;von der Weid N;Vora A;Zaliova M;Zhang L;Zichner T;Zimmermann M;Lehrach H;Borkhardt A;Bourquin JP;Franke A;Korbel JO;Stanulla M;Yaspo ML
通讯作者：
Yaspo ML
DOI：
10.1016/j.biocel.2007.05.014
发表时间：
2008-01-01
影响因子：
4
作者：
Slattery, Craig;Ryan, Michael P.;McMorro, Tara
通讯作者：
McMorro, Tara