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EPIGENETIC MODULATION OF STEMNESS AND DIFFERENTIATION BY VALPROIC ACID IN MEDULLOBLASTOMA

Abstract AIMS Changes in epigenetic processes, including histone acetylation, are proposed as key events affecting tumor cell function and the initiation and progression of pediatric brain cancers. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (H...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2024-10, Vol.26 (Supplement_7), p.vii19-vii19
Main Authors: Roesler, Prof Rafael, Freire, Ms Natalia Hogetop, de Farias, Dr Caroline Brunetto, Brunetto, Dr André, Jaeger, Dr Mariane, Brunetto, Dr Algemir, Herlinger, Dr Alice Laschuk, Gregianin, Dr Lauro
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container_issue Supplement_7
container_start_page vii19
container_title Neuro-oncology (Charlottesville, Va.)
container_volume 26
creator Roesler, Prof Rafael
Freire, Ms Natalia Hogetop
de Farias, Dr Caroline Brunetto
Brunetto, Dr André
Jaeger, Dr Mariane
Brunetto, Dr Algemir
Herlinger, Dr Alice Laschuk
Gregianin, Dr Lauro
description Abstract AIMS Changes in epigenetic processes, including histone acetylation, are proposed as key events affecting tumor cell function and the initiation and progression of pediatric brain cancers. 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 report VPA-induced alterations in features related to stemness and differentiation in medulloblastoma (MB) cells. METHOD Human MB cells were treated with different concentrations of VPA and cell viability was measured with a trypan exclusion assay. Cell cycle was evaluated with flow cytometry. Expansion of MB cancer stem cells (CSCs) was evaluated by a neurosphere formation assay. Reverse transcriptase polymerase chain reaction (RT-qPCR) was used to analyze mRNA expression and Western Blot to analyze protein levels. H3K9 histone acetylation (H3K9ac) was measured with immunofluorescence, and chromatin Immunoprecipitation (ChIP) was used to evaluate the occupancy of gene promoter regions by H3K9ac. RESULTS VPA reduced MB cell viability and expansion of MB CSCs, induced morphological changes consistent with neuronal differentiation, and increased expression of differentiation markers tubulin beta 3 class III (TUBB3) and enolase 2 (ENO2). Expression of stemness markers SOX2 and Nestin was differentially affected by VPA in cells representative of SHH or Group 3/4 MB molecular subgroups. VPA increased H3K9ac and its occupancy of promoter regions of TP53 and CDKN1A genes. CONCLUSION Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in modulation of stemness and stimulation of neuronal differentiation.
doi_str_mv 10.1093/neuonc/noae158.077
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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 report VPA-induced alterations in features related to stemness and differentiation in medulloblastoma (MB) cells. METHOD Human MB cells were treated with different concentrations of VPA and cell viability was measured with a trypan exclusion assay. Cell cycle was evaluated with flow cytometry. Expansion of MB cancer stem cells (CSCs) was evaluated by a neurosphere formation assay. Reverse transcriptase polymerase chain reaction (RT-qPCR) was used to analyze mRNA expression and Western Blot to analyze protein levels. H3K9 histone acetylation (H3K9ac) was measured with immunofluorescence, and chromatin Immunoprecipitation (ChIP) was used to evaluate the occupancy of gene promoter regions by H3K9ac. RESULTS VPA reduced MB cell viability and expansion of MB CSCs, induced morphological changes consistent with neuronal differentiation, and increased expression of differentiation markers tubulin beta 3 class III (TUBB3) and enolase 2 (ENO2). Expression of stemness markers SOX2 and Nestin was differentially affected by VPA in cells representative of SHH or Group 3/4 MB molecular subgroups. VPA increased H3K9ac and its occupancy of promoter regions of TP53 and CDKN1A genes. CONCLUSION Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in modulation of stemness and stimulation of neuronal differentiation.</description><identifier>ISSN: 1522-8517</identifier><identifier>EISSN: 1523-5866</identifier><identifier>DOI: 10.1093/neuonc/noae158.077</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><ispartof>Neuro-oncology (Charlottesville, Va.), 2024-10, Vol.26 (Supplement_7), p.vii19-vii19</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. 2024</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Roesler, Prof Rafael</creatorcontrib><creatorcontrib>Freire, Ms Natalia Hogetop</creatorcontrib><creatorcontrib>de Farias, Dr Caroline Brunetto</creatorcontrib><creatorcontrib>Brunetto, Dr André</creatorcontrib><creatorcontrib>Jaeger, Dr Mariane</creatorcontrib><creatorcontrib>Brunetto, Dr Algemir</creatorcontrib><creatorcontrib>Herlinger, Dr Alice Laschuk</creatorcontrib><creatorcontrib>Gregianin, Dr Lauro</creatorcontrib><title>EPIGENETIC MODULATION OF STEMNESS AND DIFFERENTIATION BY VALPROIC ACID IN MEDULLOBLASTOMA</title><title>Neuro-oncology (Charlottesville, Va.)</title><description>Abstract AIMS Changes in epigenetic processes, including histone acetylation, are proposed as key events affecting tumor cell function and the initiation and progression of pediatric brain cancers. 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 report VPA-induced alterations in features related to stemness and differentiation in medulloblastoma (MB) cells. METHOD Human MB cells were treated with different concentrations of VPA and cell viability was measured with a trypan exclusion assay. Cell cycle was evaluated with flow cytometry. Expansion of MB cancer stem cells (CSCs) was evaluated by a neurosphere formation assay. Reverse transcriptase polymerase chain reaction (RT-qPCR) was used to analyze mRNA expression and Western Blot to analyze protein levels. H3K9 histone acetylation (H3K9ac) was measured with immunofluorescence, and chromatin Immunoprecipitation (ChIP) was used to evaluate the occupancy of gene promoter regions by H3K9ac. RESULTS VPA reduced MB cell viability and expansion of MB CSCs, induced morphological changes consistent with neuronal differentiation, and increased expression of differentiation markers tubulin beta 3 class III (TUBB3) and enolase 2 (ENO2). Expression of stemness markers SOX2 and Nestin was differentially affected by VPA in cells representative of SHH or Group 3/4 MB molecular subgroups. VPA increased H3K9ac and its occupancy of promoter regions of TP53 and CDKN1A genes. 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RESULTS VPA reduced MB cell viability and expansion of MB CSCs, induced morphological changes consistent with neuronal differentiation, and increased expression of differentiation markers tubulin beta 3 class III (TUBB3) and enolase 2 (ENO2). Expression of stemness markers SOX2 and Nestin was differentially affected by VPA in cells representative of SHH or Group 3/4 MB molecular subgroups. VPA increased H3K9ac and its occupancy of promoter regions of TP53 and CDKN1A genes. CONCLUSION Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in modulation of stemness and stimulation of neuronal differentiation.</abstract><cop>US</cop><pub>Oxford University Press</pub><doi>10.1093/neuonc/noae158.077</doi></addata></record>
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title EPIGENETIC MODULATION OF STEMNESS AND DIFFERENTIATION BY VALPROIC ACID IN MEDULLOBLASTOMA
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