title: Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer.
abstract: 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.
authors: Department of Urology Erasmus Medical Centre, Rotterdam, The Netherlands. j.boormans@erasmusmc.nl
authors: Joost L
authors: JL
authors: Boormans
authors: Hanneke
authors: H
authors: Korsten
authors: Angelique J C
authors: AJ
authors: Ziel-van der Made
authors: Geert J L H
authors: GJ
authors: van Leenders
authors: Carola V
authors: CV
authors: de Vos
authors: Guido
authors: G
authors: Jenster
authors: Jan
authors: J
authors: Trapman
mesh_terms: D000368:Aged; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C072312:ERG protein, human; D034741:RNA, Small Interfering; C580566:TDRD1 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D017430:Prostate-Specific Antigen