Rickman David S, Pflueger Dorothee, Moss Benjamin, VanDoren Vanessa E, Chen Chen X, de la Taille Alexandre, Kuefer Rainer, Tewari Ashutosh K, Setlur Sunita R, Demichelis Francesca, Rubin Mark A
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
Cancer Res. 2009 Apr 1;69(7):2734-8. doi: 10.1158/0008-5472.CAN-08-4926. Epub 2009 Mar 17.
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).
染色体重排导致了前列腺癌中所有已报道的成红细胞转化特异性（ETS）家族成员基因融合，这些融合具有临床、诊断和预后意义。雄激素调节基因构成了与ETS基因融合的5'基因组调控启动子元件的大部分。TMPRSS2-ERG、TMPRSS2-ETV1和SLC45A3-ERG重排约占ETS融合前列腺癌的90%。ELK4是另一个ETS家族成员，受雄激素调节，参与促进细胞生长，在一部分前列腺癌中高表达，但其过表达机制尚不清楚。在本研究中，我们鉴定了一种新的ETS家族融合转录本SLC45A3-ELK4，并发现它在良性前列腺组织和前列腺癌中均有表达。我们发现高水平的SLC45A3-ELK4 mRNA仅限于一部分前列腺癌样本。在前列腺癌高危男性的尿液样本中可检测到高水平的SLC45A3-ELK4转录本。对融合mRNA的表征揭示了一个主要变体，其中SLC45A3外显子1与ELK4外显子2融合。基于DNA的定量PCR分析，与前列腺癌中描述的其他ETS融合不同，SLC45A3-ELK4 mRNA的表达并非仅限于存在染色体重排的病例。用合成雄激素（R1881）处理LNCaP癌细胞表明，SLC45A3-ELK4而非内源性ELK4的mRNA表达受雄激素调节。总之，我们的研究结果表明，SLC45A3-ELK4 mRNA表达具有异质性，在一部分前列腺癌中高度诱导，受雄激素调节，且最常见的发生机制不是染色体重排（例如，反式剪接）。
