SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities
SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities
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SET8促进上皮间质转化并赋予TWIST双重转录活性
DOI：
10.1038/emboj.2011.364
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发表时间：
2012-01-04
期刊：
影响因子：
11.4
通讯作者：
Shang, Yongfeng
中科院分区：
文献类型：
--
作者：
Yang, Fen;Sun, Luyang;Shang, Yongfeng
Set8参与转录调控、异染色质形成、基因组稳定性、细胞周期进程和发育。因此，可以预测Set8可能参与了肿瘤的发生发展。然而，Set8是否以及如何参与肿瘤的发生目前尚不清楚。在这里，我们报告了Set8在物理上与TWIST相关，TWIST是上皮-间充质转化(EMT)的主要调节因子。我们证明Set8和Twist在促进EMT和增强乳腺癌细胞体外和体内侵袭潜能方面功能上是相互依赖的。我们发现，Set8通过其H4K20单甲基化活性，对扭曲靶基因E-钙粘蛋白和N-钙粘蛋白的启动子起双重表观遗传修饰作用。在乳腺癌组织中，Set8的表达与肿瘤转移、TWIST和N-钙粘蛋白的表达呈正相关，与E-钙粘蛋白的表达呈负相关。综上所述，我们的实验揭示了Set8在肿瘤侵袭和转移中的新作用，并为扭转促进EMT提供了一个分子机制，表明Set8可能成为干预乳腺癌转移的潜在靶点。EMBO期刊(2012)31,110-123。DOI：10.1038/Intemj.2011.364；2011年10月7日在线发布
SET8 is implicated in transcriptional regulation, heterochromatin formation, genomic stability, cell-cycle progression, and development. As such, it is predicted that SET8 might be involved in the development and progression of tumour. However, whether and how SET8 might be implicated in tumourigenesis is currently unknown. Here, we report that SET8 is physically associated with TWIST, a master regulator of epithelial-mesenchymal transition (EMT). We demonstrated that SET8 and TWIST are functionally interdependent in promoting EMT and enhancing the invasive potential of breast cancer cells in vitro and in vivo. We showed that SET8 acts as a dual epigenetic modifier on the promoters of the TWIST target genes E-cadherin and N-cadherin via its H4K20 monomethylation activity. Significantly, in breast carcinoma samples, SET8 expression is positively correlated with metastasis and the expression of TWIST and N-cadherin and negatively correlated with E-cadherin. Together, our experiments revealed a novel role for SET8 in tumour invasion and metastasis and provide a molecular mechanism underlying TWIST-promoted EMT, suggesting SET8 as a potential target for intervention of the metastasis of breast cancer. The EMBO Journal (2012) 31, 110-123. doi: 10.1038/emboj.2011.364; Published online 7 October 2011