Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres.

in Cells by Natália Hogetop Freire, Alice Laschuk Herlinger, Julia Vanini, Matheus Dalmolin, Marcelo A C Fernandes, Carolina Nör, Vijay Ramaswamy, Caroline Brunetto de Farias, André Tesainer Brunetto, Algemir Lunardi Brunetto, Lauro José Gregianin, Mariane da Cunha Jaeger, Michael D Taylor, Rafael Roesler

TLDR

  • The study investigated the potential of valproic acid (VPA) as an epigenetic anticancer therapy for pediatric brain tumors and found that it reduced medulloblastoma cell viability, induced cell cycle arrest, and modified histone acetylation.
  • VPA also impaired the expansion of medulloblastoma neurospheres and modulated the expression of stemness and differentiation genes.
  • The study suggests that VPA may have antitumor effects in pediatric brain tumors by influencing histone acetylation and suggests new targets for combination therapies.

Abstract

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of theoncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reducedwhile increasingexpression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genesand. The expression of stemness genes,, andwas differentially affected by VPA in MB cells with differentstatus. VPA increased H3K9 occupancy of the promoter region of. Among the genes regulated by VPA, the stemness regulatorsandshowed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression ofand an increase in.

Overview

  • The study investigated the potential of valproic acid (VPA) as an epigenetic anticancer therapy for pediatric brain tumors.
  • VPA was shown to reduce medulloblastoma (MB) cell viability, induce cell cycle arrest, and modify histone acetylation.
  • The study aimed to determine the effects of VPA on MB cells and neurospheres, and its potential for modulating stemness, neuronal differentiation, and gene expression.

Comparative Analysis & Findings

  • VPA treatment resulted in a reduction of MB cell viability and cell cycle arrest, accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the oncogene.
  • VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced while increasing expression.
  • The expression of stemness genes and was differentially affected by VPA in MB cells with different statuses, with a decrease in stemness genes and an increase in gene expression in cells with poorer prognosis.

Implications and Future Directions

  • The study suggests that VPA may have antitumor effects in pediatric brain tumors by influencing histone acetylation, which can result in the modulation of stemness, neuronal differentiation, and expression of genes associated with patient prognosis in specific molecular subgroups.
  • Further studies are needed to determine the optimal dosing and administration schedule for VPA as an epigenetic anticancer therapy for pediatric brain tumors.
  • The identification of specific genes regulated by VPA, such as stemness regulators and, may provide new targets for the development of combination therapies for pediatric brain tumors.
Read Full Article