QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer. (16th November 2020)

• Record Type: Journal Article
• Authors: Wang, Jin-Zhu; Fu, Xing; Fang, Zhaoyuan; Liu, Hui; Zong, Feng-Yang; Zhu, Hong; Yu, Yan-Fei; Zhang, Xiao-Ying; Wang, Shen-Fei; Huang, Ying; Hui, Jingyi
• Editors: Wang, Zefeng
• Is Part Of: Journal of molecular cell biology. Volume 13:Number 5(2021)
• Page Start: 347
• Page End: 360
• Publication Date: 2020-11-16
• Subjects: ADD3 -- alternative splicing -- RNA-binding protein -- QKI -- lung cancer; Molecular biology -- Periodicals; 571.605
• DOI: 10.1093/jmcb/mjaa063
• Languages: English
• ISSNs: 1674-2788

Abstract

Abstract: Accumulating evidence indicates that the alternative splicing program undergoes extensive changes during cancer development 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.