Polycomb Protein EZH2 Regulates Tumor Invasion via the Transcriptional Repression of the Metastasis Suppressor RKIP in Breast and Prostate Cancer
Polycomb Protein EZH2 Regulates Tumor Invasion via the Transcriptional Repression of the Metastasis Suppressor RKIP in Breast and Prostate Cancer
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DOI：
10.1158/0008-5472.can-11-3546
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发表时间：
2012-06-15
期刊：
影响因子：
11.2
通讯作者：
Yeung, Kam C.
中科院分区：
文献类型：
--
作者：
Ren, Gang;Baritaki, Stavroula;Yeung, Kam C.
表观遗传修饰如组蛋白甲基化在人类癌症转移中起重要作用。zeste增强子同源物2（EZH 2）编码多梳抑制复合物2（PRC 2）的组蛋白甲基转移酶组分，其在乳腺癌和前列腺癌中广泛过表达，并在表观遗传学上使肿瘤抑制基因沉默。新的肿瘤和转移抑制因子Raf-1激酶抑制剂蛋白（RKIP）的表达水平已显示与乳腺和前列腺细胞系以及临床癌组织中EZH 2的表达水平负相关。在这里，我们发现RKIP/EZH 2比值随着疾病的严重程度显著降低，并且与乳腺癌的无复发生存率呈负相关。使用功能丧失和获得方法的组合，我们发现EZH 2通过抑制相关的组蛋白修饰负调控RKIP转录。EZH 2和zeste 12的抑制子（Suz 12）直接募集到RKIP启动子的近端E盒伴随有H3-K27-me 3和H3-K9-me 3修饰。EZH 2对RKIP表达的抑制活性依赖于组蛋白去乙酰化酶启动子的募集，并受miR-101上游负调控。总之，我们的研究结果表明EZH 2部分通过RKIP抑制加速癌细胞侵袭。这些数据还暗示EZH 2参与RKIP转录的调节，表明EZH 2促进肿瘤进展和转移的潜在机制。Cancer Res; 72（12）; 3091-104.（C）2012年AACR。
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 modifications. Direct recruitment of EZH2 and suppressor of zeste 12 (Suz12) to the proximal E-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 findings 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. Cancer Res; 72(12); 3091-104. (C)2012 AACR.