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Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness

Oncogene volume 35, pages 3163–3177 (2016)Cite this article

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Abstract

Glioblastoma is the most aggressive primary brain tumor in adults. Although the rapid recurrence of glioblastomas after treatment is a major clinical challenge, the relationships between tumor growth and intracerebral spread remain poorly understood. We have identified the cofilin phosphatase chronophin (gene name: pyridoxal phosphatase, PDXP) as a glial tumor modifier. Monoallelic PDXP loss was frequent in four independent human astrocytic tumor cohorts and increased with tumor grade. We found that aberrant PDXP promoter methylation can be a mechanism leading to further chronophin downregulation in glioblastomas, which correlated with shorter glioblastoma patient survival. Moreover, we observed an inverse association between chronophin protein expression and cofilin phosphorylation levels in glioma tissue samples. Chronophin-deficient glioblastoma cells showed elevated cofilin phosphorylation, an increase in polymerized actin, a higher directionality of cell migration, and elevated in vitro invasiveness. Tumor growth of chronophin-depleted glioblastoma cells xenografted into the immunodeficient mouse brain was strongly impaired. Our study suggests a mechanism whereby the genetic and epigenetic alterations of PDXP resulting in altered chronophin expression may regulate the interplay between glioma cell proliferation and invasion.

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Acknowledgements

We thank Andrea Odersky and Beate Vogt for excellent technical assistance and Miriam Ritz, Carolin Graf, Thorsten Winter and Katja Ottmüller for help with bioluminescence imaging. We also thank Stephan Kissler for the gift of viral vectors, Christian Linden for FACS sorting and Michael Krause and Lukas Rycak, Marburg University, for microarray analysis. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB728 to AG and GR; SFB688 and FZ82 to AG), the Forschungskommission of the Medical Faculty of Heinrich Heine University Düsseldorf (to AG) and by an IZKF Würzburg research grant (to AB). TGZ was supported by a predoctoral fellowship from the Medical Faculty of the University of Würzburg (Graduate School of Life Sciences) and by the Deutsche Forschungsgemeinschaft TR17. SK was supported by a fellowship of the Else Kröner-Fresenius-Stiftung, and CBKT is supported by the Max Eder Program of the German Cancer Aid (Deutsche Krebshilfe).

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Author notes

  1. M Schulze

    Present address: 9Current address: Department of Neuropathology, University of Regensburg, Regensburg, Germany.,

  2. O Fedorchenko

    Present address: 10Current address: Department I of Internal Medicine, Center for Integrated Oncology Cologne-Bonn, University of Cologne, Cologne, Germany.,

Authors and Affiliations

  1. Institute for Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany

    M Schulze, T G Zink, E Jeanclos & A Gohla

  2. Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany

    M Schulze, E Jeanclos & A Gohla

  3. Institute for Biochemistry and Molecular Biology II, Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    O Fedorchenko

  4. Department of Neuropathology, Heinrich Heine University, Düsseldorf, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    C B Knobbe-Thomsen & G Reifenberger

  5. Department of Internal Medicine II and Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany

    S Kraus, S Schwinn & A Beilhack

  6. Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany

    C M Monoranu

  7. Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany

    C M Monoranu

  8. Department of Neurosurgery, University of Würzburg, Würzburg, Germany

    A-L Sirén

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Correspondence to A Gohla.

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Competing interests

GR has received grants from Roche and Merck, as well as honoraria for advisory boards or lectures from Amgen, Merck and Roche. The other authors declare no conflict of interest.

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Schulze, M., Fedorchenko, O., Zink, T. et al. Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness. Oncogene 35, 3163–3177 (2016). https://doi.org/10.1038/onc.2015.376

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