Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres
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...
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2025-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Natália Hogetop Freire |
| collection | DOAJ |
| description | 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 <i>MYC</i> oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced <i>MYC</i> while increasing <i>TP53</i> expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes <i>TUBB3</i> and <i>ENO2</i>. The expression of stemness genes <i>SOX2</i>, <i>NES</i>, and <i>PRTG</i> was differentially affected by VPA in MB cells with different <i>TP53</i> status. VPA increased H3K9 occupancy of the promoter region of <i>TP53</i>. Among the genes regulated by VPA, the stemness regulators <i>MYC</i> and <i>NES</i> 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 <i>MYC</i> and an increase in <i>TP53</i>. |
| format | Article |
| id | doaj-art-765251605ae94f1da82e4f8d06704004 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-765251605ae94f1da82e4f8d067040042025-01-24T13:26:34ZengMDPI AGCells2073-44092025-01-011427210.3390/cells14020072Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma NeurospheresNatália Hogetop Freire0Alice Laschuk Herlinger1Julia Vanini2Matheus Dalmolin3Marcelo A. C. Fernandes4Carolina Nör5Vijay Ramaswamy6Caroline Brunetto de Farias7André Tesainer Brunetto8Algemir Lunardi Brunetto9Lauro José Gregianin10Mariane da Cunha Jaeger11Michael D. Taylor12Rafael Roesler13Children’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, BrazilCancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, BrazilCancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, BrazilNational Science and Technology Institute for Children’s Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre 90035-003, RS, BrazilNational Science and Technology Institute for Children’s Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre 90035-003, RS, BrazilThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaChildren’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, BrazilChildren’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, BrazilChildren’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, BrazilCancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, BrazilChildren’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, BrazilThe Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, CanadaCancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, BrazilChanges 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 <i>MYC</i> oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced <i>MYC</i> while increasing <i>TP53</i> expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes <i>TUBB3</i> and <i>ENO2</i>. The expression of stemness genes <i>SOX2</i>, <i>NES</i>, and <i>PRTG</i> was differentially affected by VPA in MB cells with different <i>TP53</i> status. VPA increased H3K9 occupancy of the promoter region of <i>TP53</i>. Among the genes regulated by VPA, the stemness regulators <i>MYC</i> and <i>NES</i> 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 <i>MYC</i> and an increase in <i>TP53</i>.https://www.mdpi.com/2073-4409/14/2/72valproic acid<i>MYC</i><i>TP53</i>stemnessdifferentiationmedulloblastoma |
| spellingShingle | 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 Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres Cells valproic acid <i>MYC</i> <i>TP53</i> stemness differentiation medulloblastoma |
| title | Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres |
| title_full | Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres |
| title_fullStr | Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres |
| title_full_unstemmed | Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres |
| title_short | Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres |
| title_sort | modulation of stemness and differentiation regulators by valproic acid in medulloblastoma neurospheres |
| topic | valproic acid <i>MYC</i> <i>TP53</i> stemness differentiation medulloblastoma |
| url | https://www.mdpi.com/2073-4409/14/2/72 |
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