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Molecular dissection of the valproic acid effects on glioma cells.

ABSTRACT: 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.

SUBMITTER: Hoja S

PROVIDER: S-EPMC5325342 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Molecular dissection of the valproic acid effects on glioma cells.

Hoja Sabine S Schulze Markus M Rehli Michael M Proescholdt Martin M Herold-Mende Christel C Hau Peter P Riemenschneider Markus J MJ

Oncotarget 20160901 39

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 p ...[more]

PMID: 27556305

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Project description:BackgroundProgressive fibrous thickening of the peritoneal membrane is a complication of long-term peritoneal dialysis (PD). TGF-β/Smad pathway activation, inflammation, and neoangiogenesis play important roles in peritoneal membrane (PM) changes induced by PD. Recently, histone deacetilase inhibitors (HDACi) have shown anti-fibrotic and anti-inflammatory effects in different experimental models. These drugs prevent deacetylation of histones causing a loosen chromatin, which in turn induce the expression of some anti-fibrotic genes. In addition, acetylation may increase the activity of proteins involved in tissue fibrosis, such as Smad7. Here, we explored the effect of valproic acid (VPA), an HDACi, on the development of peritoneal fibrosis (PF) in rats.MethodsPF was induced by daily intraperitoneal injections of 0.1% chlorhexidine gluconate (CG) for 15 consecutive days. Male Wistar rats (250-300 g) were divided into 3 groups: CONTROL, control rats receiving only vehicle; PF, peritoneal fibrosis induced in rats; PF+VPA, rats with PF treated with VPA (300 mg/kg/day by gavage). PF was assessed by Masson's trichrome staining. Inflammation and fibrosis-associated factors were assessed by immunohistochemistry, immunofluorescence, multiplex analysis, and qPCR.ResultsTreatment with VPA significantly reduced PM thickness and the expression of myofibroblasts, besides preventing loss of ultrafiltration capacity of the PM. The upregulation of profibrotic factors (TGF-β, fibronectin, and Smad3) in the PF group was significantly ameliorated by VPA. VPA modulated the TGF/Smad pathway, inhibiting phosphorylated Smad3 expression and inducing an increased Smad7 expression in the FP+VPA group. The neoangiogenesis and the expression of proinflammatory cytokines (TNF-α, IL-1β, MCP-1) observed in the PF group was significantly reduced by VPA.ConclusionsOur results indicate that VPA suppressed experimental PF through modulation of the TGF-β/Smad pathway. Interestingly, VPA treatment induced a higher expression of antifibrotic factors, such as Smad7. These results suggest that VPA may represent a potential strategy for treating long term PD complications.

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Molecular dissection of the valproic acid effects on glioma cells.

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Molecular dissection of the valproic acid effects on glioma cells.

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