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

Authors

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

Publication Date

1-7-2025

Journal

Cells

DOI

10.3390/cells14020072

PMID

39851500

PMCID

PMC11763699

PubMedCentral® Posted Date

1-7-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Valproic Acid, Humans, Medulloblastoma, Cell Differentiation, Cell Line, Tumor, Acetylation, Neoplastic Stem Cells, Tumor Suppressor Protein p53, Histones, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Cell Survival, Cerebellar Neoplasms, Cell Cycle Checkpoints, valproic acid, MYC, TP53, stemness, differentiation, medulloblastoma

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 the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2. The expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among the genes regulated by VPA, the stemness regulators MYC and NES showed 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 of MYC and an increase in TP53.

Comments

Associated Data