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Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells

Oncogene volume 35, pages 2465–2474 (2016)Cite this article

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Abstract

Oncolytic human herpes simplex virus type 1 (HSV-1) shows promising treatment efficacy in late-stage clinical trials. The anticancer activity of oncolytic viruses relies on deregulated pathways in cancer cells, which make them permissive to oncolysis. To identify pathways that restrict HSV-1 KM100-mediated oncolysis, this study used a pooled genome-wide short hairpin RNA library and found that depletion of the splicing factor arginine-rich splicing factor 2 (SRSF2) leads to enhanced cytotoxicity of breast cancer cells by KM100. Serine/arginine-rich (SR) proteins are a family of RNA-binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing. Further characterization showed that KM100 infection of HS578T cells under conditions of low SRSF2 leads to pronounced apoptosis without a corresponding increase in virus replication. As DNA topoisomerase I inhibitors can limit the phosphorylation of SRSF2, we combined a topoisomerase I inhibitor chemotherapeutic with KM100 and observed synergistic anticancer effect in vitro and prolonged survival of tumor-bearing mice in vivo.

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Acknowledgements

These studies were supported by operating grants to KLM from the Cancer Research Society and the Canadian Cancer Society Research Institute.

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Authors and Affiliations

  1. Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada

    S T Workenhe, B P Cuddington & K L Mossman

  2. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    T Ketela & J Moffat

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  1. S T Workenhe
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Correspondence to S T Workenhe or K L Mossman.

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Workenhe, S., Ketela, T., Moffat, J. et al. Genome-wide lentiviral shRNA screen identifies serine/arginine-rich splicing factor 2 as a determinant of oncolytic virus activity in breast cancer cells. Oncogene 35, 2465–2474 (2016). https://doi.org/10.1038/onc.2015.303

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