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Oncogenic Ras inhibits IRF1 to promote viral oncolysis

Oncogene volume 34, pages 3985–3993 (2015)Cite this article

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Abstract

Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1−/− MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis.

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Acknowledgements

This work was supported by grants (to KH) from the Canadian Institutes for Health Research (CIHR), the Regional Development Corporation of Newfoundland and Labrador (RDC) and Canadian Breast Cancer Foundation (CBCF). SLC was supported by a post-doctoral award from CIHR and RDC and a separate trainee award from the Beatrice Hunter Cancer Research Institute with funds provided by the Cancer Research Training Program as part of The Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR. Special thanks to Dr John Bell (Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Canada) for VSV and VSVM51R, and Nebiur E A for graphic design. We thank Susan Wakeham and Rahul-dev Kalsi for technical support.

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Authors and Affiliations

  1. Division of BioMedical Sciences, Faculty of Medicine, St John’s, Newfoundland, Canada

    Y Komatsu, N Ho, T Pongnopparat, M Licursi & K Hirasawa

  2. Department of Biochemistry, Faculty of Science, Memorial University of Newfoundland, St John’s, Newfoundland, Canada

    S L Christian

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Correspondence to K Hirasawa.

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Komatsu, Y., Christian, S., Ho, N. et al. Oncogenic Ras inhibits IRF1 to promote viral oncolysis. Oncogene 34, 3985–3993 (2015). https://doi.org/10.1038/onc.2014.331

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