QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer.
QKI-5 regulates the alternative splicing of cytoskeletal gene ADD3 in lung cancer.
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QKI-5调控肺癌细胞骨架基因ADD3的选择性剪接
DOI：
10.1093/jmcb/mjaa063
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发表时间：
2021-08-18
影响因子：
5.5
通讯作者：
Hui J
中科院分区：
文献类型：
--
作者：
Wang JZ;Fu X;Fang Z;Liu H;Zong FY;Zhu H;Yu YF;Zhang XY;Wang SF;Huang Y;Hui J
摘要 越来越多的证据表明，选择性剪接程序在癌症的发生和进展过程中经历了广泛的变化。 RNA 结合蛋白 QKI-5 经常被下调，并在肺癌中表现出抗肿瘤活性。然而，人们对QKI-5的功能靶点和调控机制知之甚少。在此，我们报告细胞骨架基因 Adducin 3 (ADD3) 的外显子 14 内含物的上调与肺癌的不良预后显着相关。 QKI-5 部分通过抑制 ADD3 外显子 14 的剪接来抑制细胞增殖和迁移。通过 iCLIP-seq 分析以核苷酸分辨率对体内 QKI-5 结合位点进行全基因组图谱，我们发现 QKI-5 以结合位置依赖性方式调节其靶 mRNA 的选择性剪接。通过与上游内含子区域的多个位点结合，QKI-5 抑制 ADD3 外显子 14 的剪接。我们还在肿瘤中发现了几个 QKI 突变，这些突变导致 QKI 靶标 ADD3 和 NUMB 的剪接失调。综上所述，我们的结果表明，QKI 介导的 ADD3 选择性剪接是肺癌相关的关键剪接事件，部分是 QKI 肿瘤抑制功能的基础。
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.
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影响因子：
11.4
作者：
通讯作者：
--
影响因子：
10.5
作者：
Hayakawa-Yano Y;Suyama S;Nogami M;Yugami M;Koya I;Furukawa T;Zhou L;Abe M;Sakimura K;Takebayashi H;Nakanishi A;Okano H;Yano M
通讯作者：
Yano M
影响因子：
--
作者：
Itoh M;Radisky DC;Hashiguchi M;Sugimoto H
通讯作者：
Sugimoto H
影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
DOI：
10.1073/pnas.1214394109
发表时间：
2012-11-20
影响因子：
11.1
作者：
Di Modugno, Francesca;Iapicca, Pierluigi;Nistico, Paola
通讯作者：
Nistico, Paola