Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen receptor.
Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen receptor.
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DOI：
10.1371/journal.pone.0006589
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发表时间：
2009-08-11
期刊：
影响因子：
3.7
通讯作者：
Hood L
中科院分区：
文献类型：
--
作者：
Lin B;Wang J;Hong X;Yan X;Hwang D;Cho JH;Yi D;Utleg AG;Fang X;Schones DE;Zhao K;Omenn GS;Hood L
雄激素受体（AR）在男性表型的发展和包括前列腺癌在内的不同人类疾病中起着重要作用。 AR可以根据细胞类型充当启动子或肿瘤抑制剂。 AR增殖响应计划已经进行了充分的研究，但尚未对其过于良好的响应计划进行彻底研究。
先前的研究发现，表达野生型AR的PC3细胞抑制生长并抑制侵袭。我们应用表达分析来识别在不同生长条件下（即有或没有雄激素和不同浓度的雄激素）在不同生长条件下表达AR（PC3-AR）的响应程序，然后应用新开发的芯片seq技术来识别该技术PC3癌症基因组中的AR结合区域。一个令人惊讶的发现是，即使没有添加雄激素（即在乙醇对照中），将模拟转染的PC3细胞与AR转染的细胞的比较也鉴定出3,452个差异表达的基因（两个折叠），这表明配体独立激活或极其低 - AR的水平雄激素激活。 CHIP-SEQ分析显示，PC3细胞的癌症基因组中有6,629个AR结合区域，其FDR（错误发现率）切断为0.05。大约22.4％（2,849中的638个）可以映射到转录起始位点（TSS）的2 kb之内。在PC3-AR细胞的AR结合区域中鉴定了三个新型的AR结合基序，其中两个共享核心共识序列CGAGCTCTTC，共同映射到AR结合区域的27.3％（1,808/6,629）。相比之下，AR结合位点的大约2.9％（190/6,629）包含规范的AR矩阵M00481，M00447和M00962（来自TransFAC数据库），这些基因主要源自雄激素依赖性细胞中的AR增殖反应基因。此外，我们在AR结合区域中确定了四个最高排名的共占选择率转录因子，其中包括TEF1（转录增强因子），GATA（GATA转录因子），OCT（八聚体转录因子）和PU1（PU.1转录因子） 。
我们的数据提供了一个有价值的数据集，以理解前列腺癌细胞中AR生长抑制反应程序的分子基础，该计划可以利用用于开发新型前列腺癌治疗策略的利用。
The androgen receptor (AR) plays important roles in the development of male phenotype and in different human diseases including prostate cancers. The AR can act either as a promoter or a tumor suppressor depending on cell types. The AR proliferative response program has been well studied, but its prohibitive response program has not yet been thoroughly studied. Previous studies found that PC3 cells expressing the wild-type AR inhibit growth and suppress invasion. We applied expression profiling to identify the response program of PC3 cells expressing the AR (PC3-AR) under different growth conditions (i.e. with or without androgens and at different concentration of androgens) and then applied the newly developed ChIP-seq technology to identify the AR binding regions in the PC3 cancer genome. A surprising finding was that the comparison of MOCK-transfected PC3 cells with AR-transfected cells identified 3,452 differentially expressed genes (two fold cutoff) even without the addition of androgens (i.e. in ethanol control), suggesting that a ligand independent activation or extremely low-level androgen activation of the AR. ChIP-Seq analysis revealed 6,629 AR binding regions in the cancer genome of PC3 cells with an FDR (false discovery rate) cut off of 0.05. About 22.4% (638 of 2,849) can be mapped to within 2 kb of the transcription start site (TSS). Three novel AR binding motifs were identified in the AR binding regions of PC3-AR cells, and two of them share a core consensus sequence CGAGCTCTTC, which together mapped to 27.3% of AR binding regions (1,808/6,629). In contrast, only about 2.9% (190/6,629) of AR binding sites contains the canonical AR matrix M00481, M00447 and M00962 (from the Transfac database), which is derived mostly from AR proliferative responsive genes in androgen dependent cells. In addition, we identified four top ranking co-occupancy transcription factors in the AR binding regions, which include TEF1 (Transcriptional enhancer factor), GATA (GATA transcription factors), OCT (octamer transcription factors) and PU1 (PU.1 transcription factor). Our data provide a valuable data set in understanding the molecular basis for growth inhibition response program of the AR in prostate cancer cells, which can be exploited for developing novel prostate cancer therapeutic strategies.
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