MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes
MEK-ERK pathway regulates EZH2 overexpression in association with aggressive breast cancer subtypes
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DOI：
10.1038/onc.2011.118
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发表时间：
2011-09-01
期刊：
影响因子：
8
通讯作者：
Ochiai, A.
中科院分区：
文献类型：
--
作者：
Fujii, S.;Tokita, K.;Ochiai, A.
EZH 2过表达发生在各种恶性肿瘤中，并与不良结局相关。到目前为止，我们已经证明EZH 2通过增加组蛋白H3 K27三甲基化来下调重要基因如E-cadherin和RUNX 3。然而，EZH 2在各种癌细胞中过表达的机制仍不清楚。在这项研究中，我们进行了EZH 2基因的启动子分析，并研究了在癌细胞中上调的生存信号是否与转录水平的过表达有关。我们还探索了导致乳腺癌中EZH 2过表达的信号通路的临床相关性，并证明了MEK-ERK 1/2-Elk-1通路导致EZH 2过表达。已知乳腺癌的三阴性和ERBB 2过表达亚型含有更快速增殖的乳腺癌细胞。与EZH 2过表达相关的信号通路与乳腺癌的两种侵袭性亚型相关。我们显示了组蛋白修饰蛋白EZH 2在癌细胞中过表达的重要性，我们的研究可以为EZH 2抑制成为更侵袭性乳腺癌的有效治疗铺平道路。Oncogene（2011）30，4118-4128; doi：10.1038/onc.2011.118; 2011年4月18日在线发表
EZH2 overexpression occurs in various malignancies and is associated with a poor outcome. We have so far demonstrated that EZH2 downregulates the important genes such as E-cadherin and RUNX3 by increasing histone H3K27 trimethylation. However, the mechanism of EZH2 overexpression in various cancer cells remains unclear. In this study we carried out a promoter analysis of the EZH2 gene and investigated whether a survival signal that is upregulated in cancer cells is related to overexpression at the transcription level. We also explored the clinical relevance of the signaling pathway that leads to EZH2 overexpression in breast cancer and demonstrated that MEK-ERK1/2-Elk-1 pathway leads to EZH2 overexpression. The triple-negative and ERBB2-overexpressing subtypes of breast cancer are known to contain more rapidly proliferating breast cancer cells. The signaling pathway connected to EZH2 overexpression was associated with both aggressive subtypes of breast cancer. We show the significance that overexpression of histone modifier protein EZH2 in cancer cells and our study could pave the way for EZH2 inhibition to become an efficient treatment for more aggressive breast cancers. Oncogene (2011) 30, 4118-4128; doi:10.1038/onc.2011.118; published online 18 April 2011