Department of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing, China.
EMBO J. 2012 Jan 4;31(1):110-23. doi: 10.1038/emboj.2011.364. Epub 2011 Oct 7.
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.
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 可能参与肿瘤的发生和发展。然而，SET8 是否以及如何参与肿瘤发生目前尚不清楚。在这里，我们报告 SET8 与 TWIST 物理相关，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 和增强乳腺癌细胞在体外和体内的侵袭潜能方面具有功能上的相互依赖性。我们表明 SET8 通过其 H4K20 单甲基化活性作为 TWIST 靶基因 E-钙粘蛋白和 N-钙粘蛋白启动子的双重表观遗传修饰物。重要的是，在乳腺癌样本中，SET8 的表达与转移以及 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。总之，我们的实验揭示了 SET8 在肿瘤侵袭和转移中的新作用，并为 TWIST 促进 EMT 的分子机制提供了依据，表明 SET8 可能成为干预乳腺癌转移的潜在靶点。
