Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells
Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells
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乳腺癌细胞中多梳蛋白 EZH2 整合雌激素和 Wnt 信号通路
DOI：
10.1128/mcb.00162-07
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发表时间：
2007-07-01
影响因子：
5.3
通讯作者：
Shang, Yongfeng
中科院分区：
文献类型：
--
作者：
Shi, Bin;Liang, Jing;Shang, Yongfeng
对于胚胎发育至关重要，polycomb group蛋白增强子zeste同源物2（EZH 2）在乳腺癌和前列腺癌中过表达，并与肿瘤的生长和侵袭有关。EZH 2过表达的致瘤机制在很大程度上是未知的。据信EZH 2作为转录阻遏物发挥其生物活性。然而，我们在这里报告，EZH 2功能在乳腺癌细胞中的基因转录激活。我们表明，EZH 2反式激活通常由雌激素和Wnt信号通路靶向的基因。我们证明EZH 2直接与雌激素受体α和β-连环蛋白物理相互作用，从而连接雌激素和Wnt信号通路，功能上增强雌激素和Writ通路的基因反式激活，并表型上促进细胞周期进程。此外，我们确定了EZH 2在其两个N-末端结构域的反式激活活性，并证明这些结构作为平台连接转录因子和介体复合物。我们的实验表明EZH 2是一个具有动态活性的双功能转录调节因子，并提供了EZH 2在肿瘤发生中的作用机制。
Essential for embryonic development, the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in breast and prostate cancers and is implicated in the growth and aggression of the tumors. The tumorigenic mechanism underlying EZH2 overexpression is largely unknown. It is believed that EZH2 exerts its biological activity as a transcription repressor. However, we report here that EZH2 functions in gene transcriptional activation in breast cancer cells. We show that EZH2 transactivates genes that are commonly targeted by estrogen and Wnt signaling pathways. We demonstrated that EZH2 physically interacts directly with estrogen receptor a and beta-catenin, thus connecting the estrogen and Wnt signaling circuitries, functionally enhances gene transactivation by estrogen and Writ pathways, and phenotypically promotes cell cycle progression. In addition, we identified the transactivation activity of EZH2 in its two N-terminal domains and demonstrated that these structures serve as platforms to connect transcription factors and the Mediator complex. Our experiments indicated that EZH2 is a dual function transcription regulator with a dynamic activity, and we provide a mechanism for EZH2 in tumorigenesis.