Abstract
Gene fusion is a common event in cancer. The fusion RNA and protein products often play causal roles in tumorigenesis and therefore represent ideal diagnostic and therapeutic targets. Formerly, fusion chimeric products in cancer were thought to be produced solely by chromosomal translocation. Here, we show that a chimeric SLC45A3-ELK4 RNA is generated in the absence of chromosomal rearrangement. We showed that it is not a product of RNA trans-splicing, but formed by cis-splicing of adjacent genes/read-through. The binding of CCCTC-binding factor (CTCF) to the insulator sequences inversely correlates with the expression of the chimera transcript. The SLC45A3-ELK4 fusion, but not wild-type, ELK4 plays important roles in regulating cell growth in both androgen-dependent and -independent prostate cancer cells. The level of the chimeric transcript correlates with disease progression, with the highest levels in prostate cancer metastases. Our results suggest that gene fusions can arise from cis-splicing of adjacent genes without corresponding DNA changes. With the absence of corresponding DNA rearrangement, chimeric fusion SLC45A3-ELK4 transcript in prostate cancer cells is generated by cis-splicing of adjacent genes/gene read-through instead of trans-splicing. SLC45A3-ELK4 controls prostate cancer cell proliferation, and the chimera level correlates with prostate cancer disease progression.
Highlights
Gene fusions are common features of human tumors [1,2,3]
We showed that the fusion transcript, but not wild-type, ELK4 played an important role in regulating prostate cancer cell proliferation, both in androgen-dependent and -independent cell lines
The chimeric RNA SLC45A3-ELK4 can be detected at much higher levels in the prostate cancer cell lines LNCaP and PC3 than in non-neoplastic prostate epithelial cells such as RWPE-1 and PrEC (Supplementary Fig. S1)
Summary
Gene fusions are common features of human tumors [1,2,3]. The assumption has been that the only mechanism by which a chimeric gene fusion product can be generated is chromosomal rearrangement. Several forms of SLC45A3-ELK4 RNA were amplified, a major form consists of exon 1 of SLC45A3 joined to the last 4 exons of ELK4. These 2 genes are located adjacent to each other on chromosome 1 band q32. FISH, array comparative genomic hybridization (CGH), or quantitative PCR (qPCR) for copy number variance did not detect obvious deletion of the genomic DNA between the 2 genes [4, 5], leaving the possibility of reciprocal chromosomal rearrangement or posttranscriptional changes
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