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The RNA-Binding Protein QKI Suppresses Cancer-Associated Aberrant Splicing

2014; Public Library of Science; Volume: 10; Issue: 4 Linguagem: Inglês

10.1371/journal.pgen.1004289

1553-7404

Feng-Yang Zong, Xing Fu, Wenjuan Wei, Ya-Ge Luo, Monika Heiner, Lijuan Cao, Zhaoyuan Fang, Rong Fang, Daru Lu, Hongbin Ji, Jingyi Hui,

RNA and protein synthesis mechanisms

Lung cancer is the leading cause of cancer-related death worldwide. Aberrant splicing has been implicated in lung tumorigenesis. However, the functional links between splicing regulation and lung cancer are not well understood. Here we identify the RNA-binding protein QKI as a key regulator of alternative splicing in lung cancer. We show that QKI is frequently down-regulated in lung cancer, and its down-regulation is significantly associated with a poorer prognosis. QKI-5 inhibits the proliferation and transformation of lung cancer cells both in vitro and in vivo. Our results demonstrate that QKI-5 regulates the alternative splicing of NUMB via binding to two RNA elements in its pre-mRNA, which in turn suppresses cell proliferation and prevents the activation of the Notch signaling pathway. We further show that QKI-5 inhibits splicing by selectively competing with a core splicing factor SF1 for binding to the branchpoint sequence. Taken together, our data reveal QKI as a critical regulator of splicing in lung cancer and suggest a novel tumor suppression mechanism involving QKI-mediated regulation of the Notch signaling pathway.