Molecular dissection of the valproic acid effects on glioma cells
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Sabine Hoja1, Markus Schulze1, Michael Rehli2,3, Martin Proescholdt4,5, Christel Herold-Mende6, Peter Hau5,7 and Markus J. Riemenschneider1,5
1 Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany
2 Department of Internal Medicine III, Regensburg University Hospital, Regensburg, Germany
3 RCI Regensburg Centre for Interventional Immunology, Regensburg University Hospital, Regensburg, Germany
4 Department of Neurosurgery, Regensburg University Hospital, Regensburg, Germany
5 Wilhelm Sander Neuro-Oncology Unit, Regensburg University Hospital, Regensburg, Germany
6 Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
7 Department of Neurology, Regensburg University, Regensburg, Germany
Markus J. Riemenschneider, email:
Keywords: brain cancer, glioblastoma, temozolomide, HDAC inhibitor, SLC transporter
Received: May 20, 2016 Accepted: August 12, 2016 Published: August 18, 2016
Many glioblastoma patients suffer from seizures why they are treated with antiepileptic agents. Valproic acid (VPA) is a histone deacetylase inhibitor that apart from its anticonvulsive effects in some retrospective studies has been suggested to lead to a superior outcome of glioblastoma patients. However, the exact molecular effects of VPA treatment on glioblastoma cells have not yet been deciphered. We treated glioblastoma cells with VPA, recorded the functional effects of this treatment and performed a global and unbiased next generation sequencing study on the chromatin (ChIP) and RNA level. 1) VPA treatment clearly sensitized glioma cells to temozolomide: A protruding VPA-induced molecular feature in this context was the transcriptional upregulation/reexpression of numerous solute carrier (SLC) transporters that was also reflected by euchromatinization on the histone level and a reexpression of SLC transporters in human biopsy samples after VPA treatment. DNA repair genes were adversely reduced. 2) VPA treatment, however, also reduced cell proliferation in temozolomide-naive cells: On the molecular level in this context we observed a transcriptional upregulation/reexpression and euchromatinization of several glioblastoma relevant tumor suppressor genes and a reduction of stemness markers, while transcriptional subtype classification (mesenchymal/proneural) remained unaltered. Taken together, these findings argue for both temozolomide-dependent and -independent effects of VPA. VPA might increase the uptake of temozolomide and simultaneously lead to a less malignant glioblastoma phenotype. From a mere molecular perspective these findings might indicate a surplus value of VPA in glioblastoma therapy and could therefore contribute an additional ratio for clinical decision making.
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