A novel androgen receptor-binding element modulates Cdc6 transcription in prostate cancer cells during cell-cycle progression.
A novel androgen receptor-binding element modulates Cdc6 transcription in prostate cancer cells during cell-cycle progression.
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DOI：
10.1093/nar/gkp510
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发表时间：
2009-08
影响因子：
14.9
通讯作者：
Fondell JD
中科院分区：
文献类型：
--
作者：
Jin F;Fondell JD
雄激素受体（AR）通过促进细胞增殖在前列腺癌的发生和发展中起着关键作用。最近的研究表明，AR是G1-S进程的主要调节因子，可能是DNA复制的许可因子，但其机制仍不明确。在这里，我们报道AR靶向人类Cdc6基因进行转录调控。Cdc6是真核细胞DNA复制的重要调控因子，在雄激素敏感的前列腺癌细胞中，雄激素或抗雄激素治疗可反向调节其mRNA的表达。AR结合在Cdc6启动子中的一个不同的雄激素反应元件（ARE）上，这是雄激素依赖性Cdc6转录所必需的功能。我们发现，在G1/S期，新型ARE的AR占据峰值与Cdc6 mRNA表达峰值同时出现。我们还在体内鉴定了一些参与ar依赖性Cdc6转录调控的共激活因子和共抑制因子，并进一步表征了配体诱导的Cdc6启动子组蛋白乙酰化和甲基化的改变。值得注意的是，AR沉默在前列腺癌细胞中显著降低Cdc6表达和雄激素依赖性细胞增殖。总之，我们的研究结果表明Cdc6是AR的关键调控靶点，并为前列腺癌细胞增殖机制提供了新的见解。
The androgen receptor (AR) plays a pivotal role in the onset and progression of prostate cancer by promoting cellular proliferation. Recent studies suggest AR is a master regulator of G1-S progression and possibly a licensing factor for DNA replication yet the mechanisms remain poorly defined. Here we report that AR targets the human Cdc6 gene for transcriptional regulation. Cdc6 is an essential regulator of DNA replication in eukaryotic cells and its mRNA expression is inversely modulated by androgen or antiandrogen treatment in androgen-sensitive prostate cancer cells. AR binds at a distinct androgen-response element (ARE) in the Cdc6 promoter that is functionally required for androgen-dependent Cdc6 transcription. We found that peak AR occupancy at the novel ARE occurs during the G1/S phase concomitant with peak Cdc6 mRNA expression. We also identified several of the coactivators and corepressors involved in AR-dependent Cdc6 transcriptional regulation in vivo and further characterized ligand-induced alterations in histone acetylation and methylation at the Cdc6 promoter. Significantly, AR silencing in prostate cancer cells markedly decreases Cdc6 expression and androgen-dependent cellular proliferation. Collectively, our results suggest that Cdc6 is a key regulatory target for AR and provide new insights into the mechanisms of prostate cancer cell proliferation.
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影响因子：
11.2
作者：
Agoulnik, IU;Vaid, A;Weigel, NL
通讯作者：
Weigel, NL
DOI：
10.1016/j.bbamcr.2008.05.006
发表时间：
2008-10-01
影响因子：
5.1
作者：
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通讯作者：
Chakrabarti, Ratna
影响因子：
4.8
作者：
Knudsen, KE;Arden, KC;Cavenee, KK
通讯作者：
Cavenee, KK
影响因子：
2.8
作者：
Majumder, Samarpan;Liu, Yuanbo;Whang, Young E.
通讯作者：
Whang, Young E.
影响因子：
10.5
作者：
Bolton, Eric C.;So, Alex Y.;Yamamoto, Keith R.
通讯作者：
Yamamoto, Keith R.