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

Maxime Blijlevens, Ida H van der Meulen-Muileman, Renée X de Menezes, Egbert F Smit, Victor W van Beusechem

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4142-4153
Number of pages12
JournalOncogene
Volume38
Issue number21
Early online date31 Jan 2019
DOIs
Publication statusPublished - 23 May 2019

Cite this