REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer.
REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer.
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DOI：
10.1093/nar/gkt921
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发表时间：
2014-01
影响因子：
14.9
通讯作者：
Flores-Morales A
中科院分区：
文献类型：
--
作者：
Svensson C;Ceder J;Iglesias-Gato D;Chuan YC;Pang ST;Bjartell A;Martinez RM;Bott L;Helczynski L;Ulmert D;Wang Y;Niu Y;Collins C;Flores-Morales A
雄激素受体（AR）是前列腺肿瘤发生的关键调节因子，其作用尚不完全清楚。我们确定了抑制因子(RE)-1沉默转录因子（REST）作为AR作用于基因抑制的中介。染色质免疫沉淀表明，AR与染色质区域结合，这些染色质区域含有众所周知的介导REST转录抑制的顺式元件，而细胞成像研究证实，REST和AR在体内紧密共定位。雄激素诱导的基因抑制还包括通过对泛素连接酶β-TRCP的作用来调节REST蛋白的周转。雄激素剥夺或AR阻断抑制剂MDV3100 （Enzalutamide）可导致神经内分泌（NE）分化，REST失活可模仿这一现象。基因表达谱显示，REST不仅可以抑制神经元基因，还可以抑制参与细胞周期进程的基因，包括极光激酶A，该基因先前被认为与ne样去势抵抗肿瘤的生长有关。前列腺癌组织微阵列分析显示，与Gleason评分无关，REST表达降低的肿瘤早期复发的可能性更高。REST在前列腺上皮中调节AR的作用，以及REST表达与前列腺切除术后疾病复发负相关的证明，需要对其在前列腺癌发生中的作用进行更深入的表征。
The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds chromatin regions containing well-characterized cis-elements known to mediate REST transcriptional repression, while cell imaging studies confirmed that REST and AR closely co-localize in vivo. Androgen-induced gene repression also involves modulation of REST protein turnover through actions on the ubiquitin ligase β-TRCP. Androgen deprivation or AR blockage with inhibitor MDV3100 (Enzalutamide) leads to neuroendocrine (NE) differentiation, a phenomenon that is mimicked by REST inactivation. Gene expression profiling revealed that REST not only acts to repress neuronal genes but also genes involved in cell cycle progression, including Aurora Kinase A, that has previously been implicated in the growth of NE-like castration-resistant tumors. The analysis of prostate cancer tissue microarrays revealed that tumors with reduced expression of REST have higher probability of early recurrence, independently of their Gleason score. The demonstration that REST modulates AR actions in prostate epithelia and that REST expression is negatively correlated with disease recurrence after prostatectomy, invite a deeper characterization of its role in prostate carcinogenesis.
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影响因子：
11.2
作者：
Vander Griend DJ;Karthaus WL;Dalrymple S;Meeker A;DeMarzo AM;Isaacs JT
通讯作者：
Isaacs JT
影响因子：
11.4
作者：
Huang, ZQ;Li, JW;Wong, JM
通讯作者：
Wong, JM
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ
影响因子：
5.3
作者：
Andreu-Vieyra, Claudia;Lai, John;Coetzee, Gerhard A.
通讯作者：
Coetzee, Gerhard A.
影响因子：
11.2
作者：
Hendriksen, Peter J. M.;Dits, Natasja F. J.;Jenster, Guido
通讯作者：
Jenster, Guido