Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4.
Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4.
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DOI：
10.1038/cddis.2013.293
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发表时间：
2013-08-15
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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通过沉默肿瘤抑制基因，表观遗传变化可以激活对癌症发展重要的信号通路。在这份报告中，我们发现了人类胃癌中wnt信号异常激活的表观遗传学贡献。CXXC 4（CXXC指蛋白4）被鉴定为EZH 2（增强子zeste同源物2）的新靶点，并且EZH 2通过下调CXXC 4表达来促进wnt信号传导的激活。CXXC 4通过抑制wnt信号通路抑制胃癌细胞的生长。相反，CXXC 4的耗竭激活wnt信号传导，并促进非肿瘤胃上皮细胞的锚定非依赖性生长。CXXC 4在胃癌组织中表达下调，其表达下调与胃癌患者预后不良相关（hazard ratio：5.053，P<0.05）。CXXC 4通过其与散乱（Dvl）的结合，稳定β-连环蛋白的破坏复合物以抑制wnt信号传导。发现CXXC 4中的两个关键氨基酸残基K161和T162对CXXC 4与Dvl的结合和CXXC 4的生长抑制作用是重要的。总之，EZH 2通过下调CXXC 4表达促进胃癌发生中wnt信号的激活。CXXC 4是EZH 2直接调控的新型潜在抑癌基因，其表达是早期胃癌患者的重要预后因子。
Through silencing tumor suppressor genes, epigenetic changes can activate signaling pathways important to cancer development. In this report, we found an epigenetic contribution to the aberrant activation of wnt signaling in human gastric cancer. CXXC4 (CXXC finger protein 4) was identified as a novel target of EZH2 (enhancer of zeste homolog 2), and EZH2 promotes the activation of wnt singaling by downregulating CXXC4 expression. CXXC4 inhibits the growth of gastric cancer cells both in vitro and in vivo through inactivating wnt signaling. In contrast, depletion of CXXC4 activates wnt signaling and promotes the anchorage-independent growth of nontumor gastric epithelial cells. CXXC4 is downregulated in gastric carcinoma tissues and its downregulation is associated with poor outcome of gastric cancer patients (hazard ratio: 5.053, P<0.05). Through its binding to dishevelled (Dvl), CXXC4 stabilizes the destruction complex of β-catenin to inhibit wnt signaling. Two critical amino acid residues in CXXC4, K161 and T162 were found to be important to its binding to Dvl and the growth inhibitory effect of CXXC4. In summary, EZH2 promotes the activation of wnt signaling in gastric carcinogenesis through the downregulation of CXXC4 expression. CXXC4 is a novel potential tumor suppressor directly regulated by EZH2, and its expression is a significant prognosis factor for patients with early stages of gastric cancer.
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影响因子：
4.8
作者：
Chen, H;Tu, SW;Hsieh, JT
通讯作者：
Hsieh, JT
影响因子：
--
作者：
Matsui, SI;LaDuca, J;Cowell, JK
通讯作者：
Cowell, JK
DOI：
10.1073/pnas.1933744100
发表时间：
2003-09-30
影响因子：
11.1
作者：
Kleer, CG;Cao, Q;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM
影响因子：
64.8
作者：
Margueron, Raphael;Reinberg, Danny
通讯作者：
Reinberg, Danny
影响因子：
64.8
作者：
Jin, Hongchuan;Sperka, Tobias;Morrison, Helen
通讯作者：
Morrison, Helen