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Tumor cell survival dependence on the DHX9 DExH-box helicase

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Abstract

The NTP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, and microRNA-mediated control, DNA replication and maintenance of genomic stability. DHX9 has also been implicated in tumor cell maintenance and drug response. Here we report that inhibition of DHX9 expression is lethal to human cancer cell lines and murine Eμ−Myc lymphomas. Using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged (6 months) suppression of DHX9 does not result in any deleterious effects at the organismal level. Body weight, blood biochemistry and histology of various tissues were comparable to control mice. Global gene expression profiling revealed that, although reduction of DHX9 expression resulted in multiple transcriptome changes, these were relatively benign and did not lead to any discernible phenotype. Our results demonstrate a robust tolerance for systemic DHX9 suppression in vivo and support the targeting of DHX9 as an effective and specific chemotherapeutic approach.

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Acknowledgements

We thank Francis Robert for performing tail-vein injections of lymphoma cells into mice. TL was supported by a Maysie MacSporran graduate studentship and fellowships from the CIHR-sponsored Chemical Biology and Systems Biology Training Programs. This work is supported by grants from the Canadian Cancer Society Research Institute (no. 701362) and National Institutes of Health (CA163291) to JP and grants from the Swedish Research Council and the Swedish Cancer Society to OL.

Author contributions

TL performed all experiments under the guidance of JP. MP provided the histopathological analysis of tissue sections. OL analyzed the gene expression data. TL and JP wrote the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    T Lee & J Pelletier

  2. Département de Pathologie et Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec

    M Paquet

  3. Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden

    O Larsson

  4. Department of Oncology, McGill University, Montreal, Quebec, Canada

    J Pelletier

  5. Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec, Canada

    J Pelletier

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  1. T Lee
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Correspondence to J Pelletier.

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Lee, T., Paquet, M., Larsson, O. et al. Tumor cell survival dependence on the DHX9 DExH-box helicase. Oncogene 35, 5093–5105 (2016). https://doi.org/10.1038/onc.2016.52

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