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.

MiR-574-5p mediates the cell cycle and apoptosis in thyroid cancer cells via Wnt/β-catenin signaling by repressing the expression of Quaking proteins

“…The suppression of QKI, as may be induced by DNA methylation in the QKI promoter region (29), has been implicated in numerous cancer types (8,30,31). In addition, miR-574-5p has been indicated to affect the regulation of QKI.…”

Notch is a critical regulator in cervical cancer by regulating Numb splicing

“…The alternative exon 12 encodes 48 amino acids within the C-terminal proline-rich region (PRR). It has previously been suggested that increased expression of the long isoform containing exon 12 promotes cell proliferation during tumorigenesis (25), whereas the short isoform inhibits cell growth (26). To further investigate the mechanism by which the Notch signaling pathway is altered, Numb expression was investigated in three pairs of cervical squamous cell carcinoma and adjacent histologically normal tissues.…”

Roles of alternative splicing in the pathogenesis of lung cancer

“…The RNA-binding protein Quaking (QKI) as a critical regulator of splicing in lung cancer is frequently down-regulated [4] . QKI-5 regulates the alternative splicing of NUMB through binding to two RNA elements of NUMB pre-mRNA, which in turn suppresses cell proliferation and blocks the activation of the Notch signaling pathway.…”

“…QKI-5 regulates the alternative splicing of NUMB through binding to two RNA elements of NUMB pre-mRNA, which in turn suppresses cell proliferation and blocks the activation of the Notch signaling pathway. The reduced QKI abundance is strongly associated with poorer prognosis [4] , and low-level nuclear QKI in non-small cell lung cancer (NSCLC) is an independent prognostic factor for disease-free survival [5] . Another study has demonstrated that RNA binding motif protein RBM5 and its homologous RBM6/10 antagonistically regulate NUMB exon 9 alternative splicing to control tumor cell proliferation and xenograft tumor growth [6] .…”