SLC45A3-ELK4 is a novel and frequent erythroblast transformation-specific fusion transcript in prostate cancer.
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).
Rickman
David S
DS
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
Pflueger
Dorothee
D
Moss
Benjamin
B
VanDoren
Vanessa E
VE
Chen
Chen X
CX
de la Taille
Alexandre
A
Kuefer
Rainer
R
Tewari
Ashutosh K
AK
Setlur
Sunita R
SR
Demichelis
Francesca
F
Rubin
Mark A
MA
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
D015514:Oncogene Proteins, Fusion; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; C540011:SLC45A3-ELK4 fusion protein, human; D045165:Testosterone Congeners; D015741:Metribolone