【摘 要】
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Accumulating evidence indicates that the alternative splicing program undergoes extensive changes during cancer develop-ment and progression.The RNA-binding protein QKI-5 is frequently downregulated and exhibits anti-tumor activity in lung cancer.Howeve-r
【机 构】
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State Key Laboratory of Molecular Biology,Center for Excellence in Molecular Cell Science,Shanghai I
论文部分内容阅读
Accumulating evidence indicates that the alternative splicing program undergoes extensive changes during cancer develop-ment and progression.The RNA-binding protein QKI-5 is frequently downregulated and exhibits anti-tumor activity in lung cancer.Howeve-r,little is known about the functional targets and regulatory mechanism of QKI-5.Here,we report that upregulation of exon 14 inclusion of cytoskeletal gene Adducin 3 (ADD3) significantly correlates with a poor prognosis in lung cancer.QKI-5 inhibits cell proliferation and migration in part through suppressing the splicing of ADD3 exon 14.Through genome-wide mapping of QKI-5 binding sites in vivo at nucleotide resolution by iCLIP-seq analysis,we found that QKI-5 regulates alternative splicing of its target mRNAs in a binding position-dependent manner.By binding to multiple sites in an upstream intron region,QKI-5 represses the splicing of ADD3 exon 14.We also identified several QKI mutations in tumors,which cause dysregulation of the splicing of QKI targets ADD3 and NUMB.Taken together,our results reveal that QKI-mediated alternative splicing of ADD3 is a key lung cancer-associated splicing event,which underlies in part the tumor suppressor function of QKI.
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