Journal article
CBMT-12. FOCAD LOSS IMPACTS MICROTUBULE ASSEMBLY, G2/M PROGRESSION AND PATIENT SURVIVAL IN ASTROCYTIC GLIOMAS
- Brand, Frank Department of Human Genetics, Hannover Medical School, Hannover, Germany
- Förster, Alisa Department of Human Genetics, Hannover Medical School, Hannover, Germany
- Kosfeld, Anne Department of Human Genetics, Hannover Medical School, Hannover, Germany
- Bucher, Martin Department of Human Genetics, Hannover Medical School, Hannover, Germany
- Thomé, Carina Neurology Clinic, and Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany
- Raab, Marc Department of Internal Medicine V, University of Heidelberg, and Clinical Cooperation Unit Molecular Hematology / Oncology, German Cancer Research Center, Heidelberg, Germany
- Westphal, Manfred Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Pietsch, Torsten University of Bonn Medical School, Department of Neuropathology, Bonn, Germany
- von Deimling, Andreas Department of Neuropathology, University of Heidelberg Medical Center, Heidelberg, Germany
- Reifenberger, Guido Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany
- Claus, Peter Department of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany
- Hentschel, Bettina Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
- Weller, Michael Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
- Weber, Ruthild Department of Human Genetics, Hannover Medical School, Hannover, Germany
- 2019-11-11
Published in:
- Neuro-Oncology. - Oxford University Press (OUP). - 2019, vol. 21, no. Supplement_6, p. vi35-vi35
English
Abstract
In search of novel genes associated with glioma pathogenesis, we have previously shown that KIAA1797/FOCAD is frequently deleted in malignant gliomas and that the encoded focadhesin functions as a tumor suppressor impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examine an association of FOCAD copy number loss with overall survival of patients with astrocytic gliomas, and address the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis, IDH mutation and MGMT promoter methylation status confirmed FOCAD loss as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, we identified tubulin beta-6 and other tubulin family members as novel focadhesin-interacting partners. We demonstrate that tubulins and focadhesin co-localize at the centrosome and that focadhesin is enriched in proximity to centrioles. Focadhesin is recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduces microtubule assembly rates, possibly explaining why focadhesin decreases cell migration. During the cell cycle, focadhesin levels peak in G2/M phase and influence time-dependent G2/M progression possibly via polo like kinase 1 phosphorylation, providing an explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1093/neuonc/noz175.134
- ISSN 1522-8517
- Persistent URL
- https://folia.unifr.ch/global/documents/218676
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