Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness
| Autor: | Antje Gohla, Knobbe-Thomsen Cb, Andreas Beilhack, Camelia M. Monoranu, Guido Reifenberger, Zink Tg, O. Fedorchenko, Stefanie Schwinn, Elisabeth Jeanclos, Markus Schulze, Anna-Leena Sirén, Sabrina Kraus |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research Brain tumor macromolecular substances Glial tumor Biology 03 medical and health sciences Mice Mice Inbred NOD Glioma Cell Line Tumor Genetics medicine Phosphoprotein Phosphatases Animals Humans Neoplasm Invasiveness Promoter Regions Genetic Molecular Biology Cell Proliferation Astrocytic Tumor Pyridoxal phosphatase Brain Neoplasms Cell migration Cofilin DNA Methylation medicine.disease 030104 developmental biology DNA methylation Cancer research Heterografts Female Glioblastoma |
| Zdroj: | Oncogene. 35(24) |
| ISSN: | 1476-5594 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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