在人類腫瘤轉(zhuǎn)移中，表觀遺傳修飾發(fā)揮著重要作用,。5月30日Cancer Research 雜志發(fā)表了Gang Ren等人的研究論文,更加深了人類對這一問題的認(rèn)識。
Zeste 同源序列2的增強(qiáng)子EZH2,，編碼多梳蛋白抑制復(fù)合體2（PRC2）中甲基轉(zhuǎn)移酶的成分,。EZH2在乳腺癌、前列腺癌中廣泛過表達(dá),，并可以表觀遺傳修飾的方式沉默腫瘤抑制因子的表達(dá),。以往研究表明，具有抑癌,、抑轉(zhuǎn)移作用的Raf-1激酶抑制蛋白（RKIP）在乳腺癌和前列腺癌細(xì)胞系及臨床標(biāo)本的表達(dá)水平與EZH2的呈負(fù)相關(guān),。等的研究表明，RKIP/EZH2的比值隨著腫瘤的惡化顯著下降,，并與乳腺癌的無復(fù)發(fā)生存率呈負(fù)相關(guān),。
結(jié)合"失去和獲得功能"實(shí)驗手段，研究者發(fā)現(xiàn)EZH2通過抑制性組蛋白修飾,，負(fù)調(diào)控RKIP的轉(zhuǎn)錄,。伴隨著H3-K27-me3 和H3-K9-me3修飾,，EZH2和zeste12的抑制子（Suz12）被直接招募到RKIP啟動子附近的E調(diào)控盒。對EZH2和RKIP表達(dá)的抑制有賴于組蛋白去乙酰酶啟動子的招募,，并被miR-101從上游加以調(diào)節(jié),。
總之，該研究顯示,，EZH2通過抑制RKIP加速了腫瘤細(xì)胞侵襲,；而且提示EZH2可能調(diào)節(jié)RKIP的轉(zhuǎn)錄。這可能是EZH2激發(fā)腫瘤演進(jìn)和轉(zhuǎn)移的新機(jī)制,。（生物谷Bioon.com)
doi:10.1016/j.cell.2011.10.017
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PMID:
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.
