Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in desmoplastic small round cell tumor Journal Article
| Authors: | Li, H.; Smolen, G. A.; Beers, L. F.; Xia, L.; Gerald, W.; Wang, J.; Haber, D. A.; Lee, S. B. |
| Article Title: | Adenosine transporter ENT4 is a direct target of EWS/WT1 translocation product and is highly expressed in desmoplastic small round cell tumor |
| Abstract: | Background: Desmoplastic Small Round Cell Tumor (DSRCT) is a highly aggressive malignancy that affects mainly adolescents and young adults. A defining charateristics of DSRCT is a specific chromosomal translocation, t(11;22)(p13;q12), that fuses EWS with WT1, leading to a production of two isoforms of chimeric transcription factor, EWS/ WT1(-KTS) and EWS/WT1(+KTS). The chimeric proteins are thought to play critical roles in various stages of oncogenesis through aberrant transcription of different genes, but only a few of these genes have been identified. Methodology/Principal Findings: We report the identification of a new target of EWS/WT1, ENT4 (equilibrative nucleoside transporter 4) which encodes a pH-dependent adenosine transporter. ENT4 is transcriptioanlly activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (Ch1P) analyses. Furthermore, ENT4 is highly and specifically expressed in primarily tumors of DSRCT as well as in DSRCT cell line, JN-DSRCT-1. Treatment of JN-DSRCT-1 cells with adenosine analogs, such as 2-chloro-2′-deoxyadenosine (2-CdA), resulted in an increased cytotoxic response in dose- and pH-depoendent manner. Conclusions/Significance: Our detailed analyses of a novel target of EWS/ WT1 in DSRCT reveal an insight into the oncogenic mechanism of EWS-fusion chromosomal translocation gene products and provide a new marker for DSRCT. Furthermore, identification of ENT4 as a highly expressed trancript in DSRCT may represent an attractive pathway for targeting chemotherapeutic drugs into DSRCT. |
| Keywords: | controlled study; human tissue; gene translocation; human cell; promoter region; genetics; dose response; metabolism; reverse transcription polymerase chain reaction; gene expression; protein targeting; transcription initiation; ph; gene product; gene function; cancer cell culture; cytotoxicity; pathology; dose-response relationship, drug; cell line, tumor; reverse transcriptase polymerase chain reaction; adenosine; chromatin immunoprecipitation; nucleotide sequence; tumor cell line; protein transport; base sequence; dna primers; wt1 protein; primer dna; rna binding protein ews; concentration response; hydrogen-ion concentration; cladribine; small cell carcinoma; desmoplastic small round cell tumor; carcinoma, small cell; rna-binding protein ews; wt1 proteins; promoter regions (genetics); equilibrative nucleoside transporter; equilibrative nucleoside transporter 4; slc29a4 protein, human; equilibrative nucleoside transport proteins |
| Journal Title: | PLoS ONE |
| Volume: | 3 |
| Issue: | 6 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2008-06-04 |
| Start Page: | e2353 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0002353 |
| PUBMED: | 18523561 |
| PROVIDER: | scopus |
| PMCID: | PMC2394657 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 11" - "Export Date: 17 November 2011" - "Molecular Sequence Numbers: GENBANK: AK092242, R13346;" - "Source: Scopus" |
