Cancer Res.:多梳蛋白EZH2调节肿瘤演进和转移

在人类肿瘤转移中，表观遗传修饰发挥着重要作用。5月30日Cancer Research 杂志发表了Gang Ren等人的研究论文,更加深了人类对这一问题的认识。

Zeste 同源序列2的增强子EZH2，编码多梳蛋白抑制复合体2（PRC2）中甲基转移酶的成分。EZH2在乳腺癌、前列腺癌中广泛过表达，并可以表观遗传修饰的方式沉默肿瘤抑制因子的表达。以往研究表明，具有抑癌、抑转移作用的Raf-1激酶抑制蛋白（RKIP）在乳腺癌和前列腺癌细胞系及临床标本的表达水平与EZH2的呈负相关。等的研究表明，RKIP/EZH2的比值随着肿瘤的恶化显著下降，并与乳腺癌的无复发生存率呈负相关。

结合"失去和获得功能"实验手段，研究者发现EZH2通过抑制性组蛋白修饰，负调控RKIP的转录。伴随着H3-K27-me3 和H3-K9-me3修饰，EZH2和zeste12的抑制子（Suz12）被直接招募到RKIP启动子附近的E调控盒。对EZH2和RKIP表达的抑制有赖于组蛋白去乙酰酶启动子的招募，并被miR-101从上游加以调节。

总之，该研究显示，EZH2通过抑制RKIP加速了肿瘤细胞侵袭；而且提示EZH2可能调节RKIP的转录。这可能是EZH2激发肿瘤演进和转移的新机制。（生物谷Bioon.com)

doi:10.1016/j.cell.2011.10.017

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Polycomb Protein EZH2 Regulates Tumor Invasion via the Transcriptional Repression of the Metastasis Suppressor RKIP in Breast and Prostate Cancer

Gang Ren, Stavroula Baritaki, Himangi Marathe, et al.

Epigenetic modifications such as histone methylation play an important role in human cancer metastasis.Enhancer of zeste homolog 2 (EZH2), which encodes the histone methyltransferase component of the polycomb repressive complex 2 (PRC2), is overexpressed widely in breast and prostate cancers and epigenetically silences tumor suppressor genes. Expression levels of the novel tumor and metastasis suppressor Raf-1 kinase inhibitor protein (RKIP) have been shown to correlate negatively with those of EZH2 in breast and prostate cell lines as well as in clinical cancer tissues. Here, we show that the RKIP/EZH2 ratio significantly decreases with the severity of disease and is negatively associated with relapse-free survival in breast cancer. Using a combination of loss- and gain-of-function approaches, we found that EZH2 negatively regulated RKIP transcription through repression-associated histone modi fications.Direct recruitment of EZH2 and suppressor of zeste 12 (Suz12) to the proximalE-boxes of the RKIP promoter was accompanied by H3-K27-me3 and H3-K9-me3 modifications. The repressing activity of EZH2 on RKIP expression was dependent on histone deacetylase promoter recruitment and was negatively regulated upstream by miR-101. Together, our fi ndings indicate that EZH2 accelerates cancer cell invasion, in part, via RKIP inhibition. These data also implicate EZH2 in the regulation of RKIP transcription, suggesting a potential mechanism by which EZH2 promotes tumor progression and metastasis.