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QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer
Jin-Zhu Wang1,† , Xing Fu2,† , Zhaoyuan Fang3,† , Hui Liu1 , Feng-Yang Zong1 , Hong Zhu1 , Yan-Fei Yu1 , Xiao-Ying Zhang1 , Shen-Fei Wang1 , Ying Huang4 , Jingyi Hui1,*
1State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
2Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences, Shanghai 201602, China
3Key Laboratory of Systems Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
4Department of General Surgery, Shanghai Key Laboratory of Biliary Tract Disease Research, State Key Laboratory of Oncogenes and Related Genes, Xinhua Hospital, Shanghai Jiao Tong University, Shanghai 200092, China
These authors contributed equally to this work.
*Correspondence to:Jingyi Hui , Email:jyhui@sibcb.ac.cn
J Mol Cell Biol, Volume 13, Issue 5, May 2021, Pages 347-360  https://doi.org/10.1093/jmcb/mjaa063
Keyword: ADD3, alternative splicing, RNA-binding protein, QKI, lung cancer

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.