A transcriptional repressor co-regulatory network governing androgen response in prostate cancers
A transcriptional repressor co-regulatory network governing androgen response in prostate cancers
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DOI：
10.1038/emboj.2012.112
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发表时间：
2012-06-13
期刊：
影响因子：
11.4
通讯作者：
Cheung, Edwin
中科院分区：
文献类型：
--
作者：
Chng, Kern Rei;Chang, Cheng Wei;Cheung, Edwin
转录辅抑制因子在前列腺癌中经常异常过表达。然而，它们与雄激素受体（AR）的相互作用尚不清楚，雄激素受体是前列腺癌发展的关键因素。利用ChIP-Seq，我们在前列腺癌细胞中生成了广泛的AR、ERG和常见过表达的转录共抑制因子（包括HDAC1、HDAC2、HDAC3和EZH2）的全球结合图谱。令人惊讶的是，我们的研究结果显示ERG、hdac和EZH2直接参与雄激素调控的转录，并通过远端增强子和/或近端启动子的频谱连接到AR中心的转录网络中。此外，我们发现与ERG类似，这些辅抑制因子可以介导ar诱导的转录抑制，包括促进上皮分化和抑制转移的细胞骨架基因。具体来说，我们证明了ERG、EZH2和hdac直接抑制Vinculin的表达导致前列腺癌细胞的侵袭性增强。综上所述，我们的研究结果强调了一种新的机制，通过这种机制，ERG与包括hdac和多梳蛋白EZH2在内的致癌辅助抑制因子共同作用，可以通过直接调节AR的转录输出来阻止上皮细胞分化并促进前列腺癌的进展。EMBO杂志（2012）31,2810-2823。doi: 10.1038 / emboj.2012.112;2012年4月24日在线发布
Transcriptional corepressors are frequently aberrantly over-expressed in prostate cancers. However, their crosstalk with the Androgen receptor (AR), a key player in prostate cancer development, is unclear. Using ChIP-Seq, we generated extensive global binding maps of AR, ERG, and commonly over-expressed transcriptional corepressors including HDAC1, HDAC2, HDAC3, and EZH2 in prostate cancer cells. Surprisingly, our results revealed that ERG, HDACs, and EZH2 are directly involved in androgen-regulated transcription and wired into an AR centric transcriptional network via a spectrum of distal enhancers and/or proximal promoters. Moreover, we showed that similar to ERG, these corepressors function to mediate repression of AR-induced transcription including cytoskeletal genes that promote epithelial differentiation and inhibit metastasis. Specifically, we demonstrated that the direct suppression of Vinculin expression by ERG, EZH2, and HDACs leads to enhanced invasiveness of prostate cancer cells. Taken together, our results highlight a novel mechanism by which, ERG working together with oncogenic corepressors including HDACs and the polycomb protein, EZH2, could impede epithelial differentiation and contribute to prostate cancer progression, through directly modulating the transcriptional output of AR. The EMBO Journal (2012) 31, 2810-2823. doi:10.1038/emboj.2012.112; Published online 24 April 2012