Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers
Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers
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DOI：
10.1016/j.molcel.2011.08.011
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发表时间：
2011-09-02
期刊：
影响因子：
16
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Lee, Shuet Theng;Li, Zhimei;Yu, Qiang
EZH2和NF-kappa B都与侵袭性乳腺癌有关，但这两种致癌因子在乳腺癌中是否存在功能性串扰尚不清楚。在这里，我们发现EZH2在er阴性基底样乳腺癌细胞中赋予NF-kappa B靶基因表达的组成性激活的意想不到的作用。EZH2的这种功能独立于其组蛋白甲基转移酶活性，但需要与RelA/RelB物理相互作用来促进NF-kappa B靶点的表达。有趣的是，EZH2在ER阳性发光样乳腺癌细胞中起相反的作用，通过与ER相互作用并指导其启动子上的抑制性组蛋白甲基化来抑制NF-kappa B靶基因的表达。因此，EZH2在乳腺癌中作为双关节面分子发挥作用，根据细胞环境，作为nf - κ B靶点的转录激活因子或抑制因子。这些发现揭示了EZH2促进乳腺癌进展的另一种机制，并强调了开发针对乳腺癌的EZH2治疗靶向策略的必要性。
Both EZH2 and NF-kappa B contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional crosstalk in breast cancer is unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-kappa B target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-kappa B targets. Intriguingly, EZH2 acts oppositely in ER-positive luminal-like breast cancer cells and represses NF-kappa B target gene expression by interacting with ER and directing repressive histone methylation on their promoters. Thus, EZH2 functions as a double-facet molecule in breast cancers, either as a transcriptional activator or repressor of NF-kappa B targets, depending on the cellular context. These findings reveal an additional mechanism by which EZH2 promotes breast cancer progression and underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.