title: SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer.
abstract: Chromosomal rearrangements account for all erythroblast transformation-specific (ETS) family member gene fusions that have been reported in prostate cancer and have clinical, diagnostic, and prognostic implications. Androgen-regulated genes account for the majority of the 5' genomic regulatory promoter elements fused with ETS genes. TMPRSS2-ERG, TMPRSS2-ETV1, and SLC45A3-ERG rearrangements account for roughly 90% of ETS fusion prostate cancer. ELK4, another ETS family member, is androgen regulated, involved in promoting cell growth, and highly expressed in a subset of prostate cancer, yet the mechanism of ELK4 overexpression is unknown. In this study, we identified a novel ETS family fusion transcript, SLC45A3-ELK4, and found it to be expressed in both benign prostate tissue and prostate cancer. We found high levels of SLC45A3-ELK4 mRNA restricted to a subset of prostate cancer samples. SLC45A3-ELK4 transcript can be detected at high levels in urine samples from men at risk for prostate cancer. Characterization of the fusion mRNA revealed a major variant in which SLC45A3 exon 1 is fused to ELK4 exon 2. Based on quantitative PCR analyses of DNA, unlike other ETS fusions described in prostate cancer, the expression of SLC45A3-ELK4 mRNA is not exclusive to cases harboring a chromosomal rearrangement. Treatment of LNCaP cancer cells with a synthetic androgen (R1881) revealed that SLC45A3-ELK4, and not endogenous ELK4, mRNA expression is androgen regulated. Altogether, our findings show that SLC45A3-ELK4 mRNA expression is heterogeneous, highly induced in a subset of prostate cancers, androgen regulated, and most commonly occurs through a mechanism other than chromosomal rearrangement (e.g., trans-splicing).
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Rickman
authors.forename: Dorothee
authors.initials: D
authors.lastname: Pflueger
authors.forename: Benjamin
authors.initials: B
authors.lastname: Moss
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: VanDoren
authors.forename: Chen X
authors.initials: CX
authors.lastname: Chen
authors.forename: Alexandre
authors.initials: A
authors.lastname: de la Taille
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuefer
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Tewari
authors.forename: Sunita R
authors.initials: SR
authors.lastname: Setlur
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D045165:Testosterone Congeners / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; C540011:SLC45A3-ELK4 fusion protein, human; D045165:Testosterone Congeners; D015741:Metribolone