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


ABSTRACT: 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.

SUBMITTER: Zong FY 

PROVIDER: S-EPMC3983035 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Zong Feng-Yang FY   Fu Xing X   Wei Wen-Juan WJ   Luo Ya-Ge YG   Heiner Monika M   Cao Li-Juan LJ   Fang Zhaoyuan Z   Fang Rong R   Lu Daru D   Ji Hongbin H   Hui Jingyi J  

PLoS genetics 20140410 4


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 proliferat  ...[more]

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