title: Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness.
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.
authors.affiliation: Institute for Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schulze
authors.affiliation: Institute for Biochemistry and Molecular Biology II, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Fedorchenko
authors.affiliation: Institute for Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
authors.forename: T G
authors.initials: TG
authors.lastname: Zink
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C B
authors.initials: CB
authors.lastname: Knobbe-Thomsen
authors.affiliation: Department of Internal Medicine II and Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kraus
authors.affiliation: Department of Internal Medicine II and Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schwinn
authors.affiliation: Department of Internal Medicine II and Center for Interdisciplinary Clinical Research, University of Würzburg, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Department of Neuropathology, Heinrich Heine University, Düsseldorf, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Department of Neuropathology, Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Monoranu
authors.affiliation: Department of Neurosurgery, University of Würzburg, Würzburg, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Sirén
authors.affiliation: Institute for Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Jeanclos
authors.affiliation: Institute for Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.|Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gohla
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D019175:DNA Methylation; D005260:Female; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009361:Neoplasm Invasiveness; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: C496428:PDXP protein, human; D010749:Phosphoprotein Phosphatases