High-throughput RNAi screening reveals cancer-selective lethal targets in the RNA spliceosome

• Published in: Oncogene Vol. 38; no. 21; pp. 4142 - 4153
• Main Authors: Blijlevens, Maxime, van der Meulen-Muileman, Ida H., de Menezes, Renée X., Smit, Egbert F., van Beusechem, Victor W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2019; Nature Publishing Group
• Subjects: 13/2; 13/31; 13/89; 14; 38/77; 38/90; 631/1647/2163; 631/337/505; 631/67/1059/602; 631/67/1612/1350; 631/67/69; A549 Cells; Apoptosis; Apoptosis - genetics; Cancer; Cancer research; Cancer screening; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Line; Cell Line, Tumor; Cell viability; Epithelial cells; Epithelial Cells - pathology; Fibroblasts; Fibroblasts - pathology; Genetic aspects; Genetic research; High-throughput screening; High-Throughput Screening Assays - methods; Human Genetics; Humans; Internal Medicine; Libraries; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Proteins; RNA; RNA interference; RNA Interference - physiology; RNA splicing; RNA Splicing - genetics; RNA, Small Interfering - genetics; RNA-mediated interference; siRNA; Sm proteins; snRNA; Spliceosomes - genetics; Splicing; Up-Regulation - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0711-z

Novel therapeutic strategies for non-small-cell lung cancer (NSCLC) are urgently needed. RNA splicing, orchestrated by the spliceosome, is deregulated in many forms of cancer, including NSCLC. Here, we performed high-throughput screening with a small interfering RNA library targeting all annotated human spliceosome proteins to identify cancer-selective lethal targets in the RNA splicing machinery. Silencing of several spliceosome proteins reduced cell viability in a panel of NSCLC cell lines, but not in non-malignant lung fibroblasts and epithelial cells. Interestingly, the cancer-selective lethal target set comprised all seven Sm proteins that, together with small nuclear RNA, form the core structure of most spliceosome subunits. Interfering with Sm protein expression induced apoptosis in NSCLC cells, but not in non-malignant cells. In silico analysis revealed that Sm proteins are frequently upregulated in NSCLC. For several Sm proteins, increased expression showed a positive correlation with disease severity. Together, our results suggest that the Sm proteins represent particularly useful novel targets for selective treatment of NSCLC.