QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer  

作　　者：Jin-Zhu Wang Xing Fu Zhaoyuan Fang Hui Liu Feng-Yang Zong Hong Zhu Yan-Fei Yu Xiao-Ying Zhang Shen-Fei Wang Ying Huang jingyi Hui 

机构地区：[1]State 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 [2]Shanghai Center for Plant Stress Biology,Chinese Academy of Sciences,Shanghai 201602,China [3]Key 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 [4]Department 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

出　　处：《Journal of Molecular Cell Biology》2021年第5期347-360,共14页分子细胞生物学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(31661143035,31770881,and 32071288);the National Basic Research Program of China(2017YFA0504400)to J.H.

摘　　要：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.

关 键 词：ADD3t alternative splicing RNA-binding protein QKI lung cancer 

分 类 号：R73[医药卫生—肿瘤]