Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3

Abstract

Background:Fibroblast growth factor 21, a novel regulator of glucose and lipid metabolism, has robust protective properties in neurons. However, its expression and function in glia are unknown. Valproic acid, a mood stabilizer and anticonvulsant, is a histone deacetylase inhibitor and a dynamic gene regulator. We investigated whether histone deacetylase inhibition by valproic acid and other inhibitors upregulates fibroblast growth factor 21 expression and, if so, sought to identify the histone deacetylase isoform(s) involved and their role in altering glial cell morphology.Methods:C6 glioma or primary cortical glial cultures were treated with histone deacetylase inhibitors, and fibroblast growth factor 21 levels and length of cell processes were subsequently measured. Histone deacetylase 1, 2, or 3 was also knocked down to detect which isoform was involved in regulating fibroblast growth factor 21 mRNA levels. Finally, knockdown and overexpression of fibroblast growth factor 21 were performed to determine whether it played a role in regulating cell process length.Results:Treatment of C6 cells or primary glial cultures with valproic acid elevated fibroblast growth factor 21 mRNA levels, extended cell process length, and markedly increased acetylated histone-H3 levels. Other histone deacetylase inhibitors including pan- and class I-specific inhibitors, or selective knockdown of histone deacetylase 2 or 3 isoform produced similar effects. Knockdown or overexpression of fibroblast growth factor 21 significantly decreased or increased C6 cell process length, respectively.Conclusions:In glial cell line and primary glia, using pharmacological inhibition and selective gene silencing of histone deacetylases to boost fibroblast growth factor 21 mRNA levels results in elongation of cell processes. Our study provides a new mechanism via which histone deacetylase 2 and 3 participate in upregulating fibroblast growth factor 21 transcription and extending process outgrowth in glia.

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

“…In addition, VPA at a concentration of 750 µM did not radiosensitize the three human glioblastoma cell lines and three primary glioblastoma spheroid cultures studied in delayed plating colony formation assays and pre-plating limited dilution assays, respectively. These results were unexpected in light of the reported chromatin remodeling action of VPA [18, 48-50] and contradictory to previous in vitro studies [10-15, 17, 48, 51, 52] which clearly show VPA-induced cell death or radio- or chemosensitization in cancer cells including glioma. Unlike the present work, VPA concentrations of 1-5 mM [52], 1.5-2 mM [10], 1-5 mM [51], 2.5-5 mM [11], 1.5-3 mM [12], 1-15 mM [13], 2-16 mM [14], 7.5 mM [18], 2 mM [19], 5-20 mM [53], 1-10 mM [21], or 4.8 mM [22] were applied in these studies.…”

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Thirty-eight articles met all the inclusion criteria; studies retrieved for the review were organized in a flow diagram ( Figure 2). Twenty-one described studies of rodent samples (Tremolizzo et al, 2002;Dong et al, 2005;Tremolizzo et al, 2005;Kim et al, 2008;Dong et al, 2010;Hobara et al, 2010;Perisic et al, 2010;Matrisciano et al, 2011;Wang et al, 2012;Zimmermann et al, 2012;Calabrese et al, 2013;Leng et al, 2013;Ookubo et al, 2013;Liu et al, 2014;Mackowiak et al, 2014;Balasubramanian et al, 2015;Bator et al, 2015;Dwivedi and Zhang, 2015;Lee et al, 2015;Leng et al, 2016;Bahna and Niles, 2017). Seven articles studied human cell lines (Asai et al, 2013;Kao et al, 2013;Dyrvig et al, 2017;Zong et al, 2017;Billingsley et al, 2018;Dyrvig et al, 2019;Manca et al, 2019) and eight focused on blood samples of subjects diagnosed with either of the selected psychiatric disorders (Gavin et al, 2009;D'Addario et al, 2012;Dell'Osso et al, 2014;Huzayyin et al, 2014;Burghardt et al, 2015;Burghardt et al, 2016;Houtepen et al, 2016;Bengesser et al, 2018).…”

“…Rodent Models SCZ-like epigenetic modifications and symptoms, namely positive, negative, and cognitive, have been replicated in VPA induces an upregulation of the MT1 receptor through a mechanism involving histone H3 acetylation on the MT1 promoter. (Leng et al, 2016) To investigate the association between FGF21 expression and mood stabilizer's histone deacetylase inhibition in glial cells as well as to identify the HDAC isoform(s) involved in the process.…”

“…Histone H3 methylation and acetylation were induced by VPA and Li; for Li, a more pronounced demethylation of H3 was observed. Another gene involved in metabolism, fibroblast growth factor 21 (FGF21), and its effect after exposure to VPA, CBZ, LTG, and Li was studied by Leng et al (2016) in rat primary cortical glial cells and C6 glioma cells. C6 and glial cells treated with either VPA or Li experienced a dose-dependent increase in FGF21 mRNA levels, while LTG and CBZ were ineffective.…”

“…C6 and glial cells treated with either VPA or Li experienced a dose-dependent increase in FGF21 mRNA levels, while LTG and CBZ were ineffective. VPA, LTG and, less potently, CBZ significantly increased H3 acetylation levels (Leng et al, 2016). In another study, further examination of the mechanisms underlying melatonin MT 1 receptors' upregulation by VPA was performed in rat glioma cells (Bahna and Niles, 2017).…”