Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer
Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer
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DOI：
10.1002/ijc.28025
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发表时间：
2013-07-15
影响因子：
6.4
通讯作者：
Trapman, Jan
中科院分区：
文献类型：
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作者：
Boormans, Joost L.;Korsten, Hanneke;Trapman, Jan
ERG重排前列腺癌的分子分类阐明了TMPRSS 2-ERG在前列腺癌发展和进展中的作用。本研究的目的是确定ERG重排前列腺癌中的直接ERG靶基因。分析两个独立的原发性前列腺癌队列（队列A，n=48;队列B，n=31）、一个晚期前列腺癌队列（n=51）和来自不同研究所的一个原发性前列腺肿瘤队列（n=128）的表达阵列数据，以确定与ERG过表达共表达的基因的表达。通过全基因组表达分析和Q-RT-PCR显示，在A和B队列中，基因Tudor domain containing 1（TDRD 1）是迄今为止与ERG过表达最强的相关基因。来自不同研究所的患者队列的表达阵列分析显示，与ERG过表达正相关的基因（包括TDRD 1）存在很大的重叠。在晚期前列腺癌中，TDRD 1也与ERG过表达共表达，尽管有一部分ERG阴性的晚期样本表达TDRD 1。TDRD 1表达与ETV 1过表达无关。在前列腺癌细胞系VCaP中，通过shRNA下调ERG导致TDRD 1的表达水平降低，并导致TDRD 1启动子活性降低。通过突变分析，我们确定了一个功能性ERG结合位点的TDRD 1启动子。我们的研究结果表明TDRD 1是第一个被鉴定的上调的直接ERG靶基因，与原发性前列腺癌中的ERG过表达密切相关。
Molecular classification of ERG-rearranged prostate cancer clarifies the role of TMPRSS2-ERG in the development and progression of prostate cancer. The objective of our study was to identify direct ERG target genes in ERG-rearranged prostate cancer. Two independent cohorts of primary prostate cancer (Cohort A, n=48; Cohort B, n=31), a cohort of late-stage prostate cancer (n=51) and expression array data of a cohort of primary prostate tumors from a different institute (n=128) were analyzed for expression of genes that were coexpressed with ERG overexpression. By genome-wide expression analysis and Q-RT-PCR it was shown that the gene Tudor domain containing 1 (TDRD1) was by far the strongest correlated gene with ERG overexpression in both Cohort A and B. Expression array analysis of the patient cohort from a different institute showed a large overlap in genes that were positively correlated with ERG overexpression, including TDRD1. In late-stage prostate cancer, TDRD1 was also coexpressed with ERG overexpression, although a proportion of ERG-negative late-stage samples expressed TDRD1. TDRD1 expression was not associated with ETV1 overexpression. In the prostate cancer cell line VCaP, downregulation of ERG by shRNA lead to a lower expression level of TDRD1 and resulted in a decreased activity of the TDRD1 promoter. By mutation analysis we identified a functional ERG binding site in the TDRD1 promoter. Our findings show TDRD1 as the first identified upregulated direct ERG target gene that is strongly associated with ERG overexpression in primary prostate cancer.