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 Inuyasha 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 Colanders 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.