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Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma

Oncogene volume 36, pages 6006–6019 (2017)Cite this article

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Abstract

We provide evidence that the IFN-regulated member of the Schlafen (SLFN) family of proteins, SLFN5, promotes the malignant phenotype in glioblastoma multiforme (GBM). Our studies indicate that SLFN5 expression promotes motility and invasiveness of GBM cells, and that high levels of SLFN5 expression correlate with high-grade gliomas and shorter overall survival in patients suffering from GBM. In efforts to uncover the mechanism by which SLFN5 promotes GBM tumorigenesis, we found that this protein is a transcriptional co-repressor of STAT1. Type-I IFN treatment triggers the interaction of STAT1 with SLFN5, and the resulting complex negatively controls STAT1-mediated gene transcription via interferon stimulated response elements. Thus, SLFN5 is both an IFN-stimulated response gene and a repressor of IFN-gene transcription, suggesting the existence of a negative-feedback regulatory loop that may account for suppression of antitumor immune responses in glioblastoma.

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Acknowledgements

The work was supported in part by NIH grants CA161196, CA77816 and CA155566 and by grant 5I01CX000916 from the Department of Veterans Affairs. ADA was supported in part by NIH training grant T32CA070085, DS was supported in part by NIH training grant T32CA080621, and PL was supported in part by National Science Centre, Poland Grant 2016/22/M/NZ2/00548. We thank Dr John A. Kessler for providing the JK18 and JK46 GSC lines.

Data and materials availability

The microarray data was deposited to the Gene Expression Omnibus (GEO) repository under accession number GSE88771. The RNA-Seq data was deposited to the NCBI's Sequence Read Archive (SRA) repository under the registered BioProject PRJNA341338. The authors declare that all data supporting the findings of this study are available within the article and its Supplementary Information files are available from the corresponding author upon request.

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Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA

    A D Arslan, A Sassano, D Saleiro, E M Kosciuczuk, M Fischietti, F Eckerdt & L C Platanias

  2. Division of Hematology–Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    A D Arslan, A Sassano, D Saleiro, E M Kosciuczuk, M Fischietti & L C Platanias

  3. Department of Medical Genetics, Centre for Preclinical Research and Technology (CePT), Warsaw Medical University, Warsaw, Poland

    P Lisowski

  4. iPS Cell-Based Disease Modeling Group, Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany

    P Lisowski

  5. Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL, USA

    E M Kosciuczuk & L C Platanias

  6. Toronto Research Institute, University Health Network, Toronto, Ontario, Canada

    E N Fish

  7. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    E N Fish

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  1. A D Arslan
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Correspondence to L C Platanias.

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Arslan, A., Sassano, A., Saleiro, D. et al. Human SLFN5 is a transcriptional co-repressor of STAT1-mediated interferon responses and promotes the malignant phenotype in glioblastoma. Oncogene 36, 6006–6019 (2017). https://doi.org/10.1038/onc.2017.205

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