The polycomb group protein EZH2 is involved in progression of prostate cancer
The polycomb group protein EZH2 is involved in progression of prostate cancer
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DOI：
10.1038/nature01075
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发表时间：
2002-10-10
期刊：
影响因子：
64.8
通讯作者：
Chinnaiyan, AM
中科院分区：
文献类型：
--
作者：
Varambally, S;Dhanasekaran, SM;Chinnaiyan, AM
前列腺癌是男性癌症相关死亡的主要原因，仅次于肺癌。虽然临床上存在有效的手术和放疗治疗局限性前列腺癌，但转移性前列腺癌仍然基本上无法治愈。通过基因表达谱分析(1)，我们发现zeste同源物2 （EZH2）的多梳组蛋白增强子（2,3）在激素难治性转移性前列腺癌中过度表达。靶向EZH2的小干扰RNA （siRNA）双链物(4)可降低前列腺细胞中EZH2蛋白的含量，并在体外抑制细胞增殖。前列腺细胞中EZH2的异位表达诱导了一组特定基因的转录抑制。EZH2介导的基因沉默需要SET结构域，并通过抑制组蛋白去乙酰化酶活性而减弱。转移性前列腺癌中EZH2信使RNA和EZH2蛋白的表达均升高；此外，临床上局部表达EZH2浓度较高的前列腺癌预后较差。因此，EZH2表达失调可能与前列腺癌的进展有关，也是区分惰性前列腺癌与有致死进展风险的前列腺癌的标志物。
Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling(1), that the polycomb group protein enhancer of zeste homolog 2 (EZH2)(2,3) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes(4) targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.