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EZH2 通过下调CXXC 指蛋白 4 激活 Wnt 信号通路。

Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4.

机构信息

Laboratory of Cancer Biology, Biomedical Research Center, Sir Runrun Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.

出版信息

Cell Death Dis. 2013 Aug 15;4(8):e776. doi: 10.1038/cddis.2013.293.

DOI:10.1038/cddis.2013.293
PMID:23949225
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3763454/
Abstract

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 signaling 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.

摘要

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很重要的信号通路。在本报告中，我们发现了表观遗传对人类胃癌中 wnt 信号异常激活的贡献。CXXC4（CXXC 指蛋白 4）被鉴定为 EZH2（增强子的 zeste 同源物 2）的一个新靶点，EZH2 通过下调 CXXC4 表达促进 wnt 信号的激活。CXXC4 通过使 wnt 信号失活，在体外和体内抑制胃癌细胞的生长。相比之下，CXXC4 的耗竭激活了 wnt 信号，并促进了非肿瘤胃上皮细胞的无锚定生长。CXXC4 在胃癌组织中下调，其下调与胃癌患者的不良预后相关（风险比：5.053，P<0.05）。CXXC4 通过与 Dvl（dishevelled）结合，稳定 β-连环蛋白的破坏复合物，抑制 wnt 信号。CXXC4 中两个关键的氨基酸残基 K161 和 T162 对于其与 Dvl 的结合和 CXXC4 的生长抑制作用很重要。总之，EZH2 通过下调 CXXC4 表达促进胃癌发生过程中的 wnt 信号激活。CXXC4 是一个受 EZH2 直接调控的新的潜在肿瘤抑制因子，其表达是早期胃癌患者的一个重要预后因素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/cc0977de57b6/cddis2013293f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/0cd025268b08/cddis2013293f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/0926f357af98/cddis2013293f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/f44b267cdb86/cddis2013293f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/da0a40b3f909/cddis2013293f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/a18bad4a94a9/cddis2013293f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/cc0977de57b6/cddis2013293f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/0cd025268b08/cddis2013293f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/0926f357af98/cddis2013293f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/f44b267cdb86/cddis2013293f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/da0a40b3f909/cddis2013293f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/a18bad4a94a9/cddis2013293f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5607/3763454/cc0977de57b6/cddis2013293f6.jpg

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