Chimeric transcript generated by cis-splicing of adjacent genes regulates prostate cancer cell proliferation.
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.


CONCLUSIONS
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.
Department of Pathology, University of Virginia, Charlottesville, Virginia 22908, USA.
Yanmei
Y
Zhang
Mei
M
Gong
Huiling
H
Yuan
Hong G
HG
Park
Henry F
HF
Frierson
Hui
H
Li
D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D000076246:CCCTC-Binding Factor; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D015741:Metribolone / Q000494:pharmacology; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D012326:RNA Splicing; D012334:RNA, Neoplasm / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D050808:ets-Domain Protein Elk-4 / Q000235:genetics*
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004273:DNA, Neoplasm; C494193:ELK4 protein, human; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D012334:RNA, Neoplasm; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C551031:SLC45a3 protein, human; D050808:ets-Domain Protein Elk-4; D015741:Metribolone