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 characteristic 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 transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses. Furthermore, ENT4 is highly and specifically expressed in primary tumors of DSRCT as well as in a 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-dependent 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 transcript in DSRCT may represent an attractive pathway for targeting chemotherapeutic drugs into DSRCT.

• Authors: Hongjie Li, Gromoslaw A Smolen, Lisa F Beers, Li Xia, William Gerald, Joanne Wang, Daniel A Haber, Sean Bong Lee
• Journal: PloS one (PLoS One) Vol. 3 Issue 6 Pg. e2353 (Jun 04 2008) ISSN: 1932-6203 [Electronic] United States
• PMID: 18523561 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• DNA Primers
• Equilibrative Nucleoside Transport Proteins
• RNA-Binding Protein EWS
• SLC29A4 protein, human
• WT1 Proteins
• Adenosine

Topics

• Adenosine (metabolism)
• Base Sequence
• Carcinoma, Small Cell (metabolism, pathology)
• Cell Line, Tumor
• Chromatin Immunoprecipitation
• DNA Primers
• Dose-Response Relationship, Drug
• Equilibrative Nucleoside Transport Proteins (genetics, metabolism)
• Humans
• Hydrogen-Ion Concentration
• Promoter Regions, Genetic
• Protein Transport
• RNA-Binding Protein EWS (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• WT1 Proteins (metabolism)