The RNA-binding protein QKI suppresses cancer-associated aberrant splicing

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 alter...

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Bibliographic Details
Published in:PLoS genetics 2014-04, Vol.10 (4), p.e1004289
Main Authors: Zong, Feng-Yang, Fu, Xing, Wei, Wen-Juan, Luo, Ya-Ge, Heiner, Monika, Cao, Li-Juan, Fang, Zhaoyuan, Fang, Rong, Lu, Daru, Ji, Hongbin, Hui, Jingyi
Format: Article
Language:English
Subjects:
Alternative Splicing - genetics
Binding proteins
Biology and life sciences
Cancer
Cell growth
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic - genetics
Competition
Down-Regulation - genetics
Gene expression
Genes, Tumor Suppressor
Genetic aspects
Genetic research
Genomes
Health aspects
Humans
Lung cancer
Lung Neoplasms - genetics
Medical prognosis
Membrane Proteins - genetics
Nerve Tissue Proteins - genetics
Oncology, Experimental
Proteins
Receptors, Notch - genetics
RNA - genetics
RNA Precursors - genetics
RNA sequencing
RNA Splicing - genetics
RNA, Messenger - genetics
RNA-Binding Proteins - genetics
Rodents
Signal Transduction - genetics
Standard deviation
Studies
Tumor Suppressor Proteins - genetics
Tumorigenesis
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1004289