Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres
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
Affiliations
Natália Hogetop Freire
Children’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, Brazil
Alice Laschuk Herlinger
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
Julia Vanini
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
Matheus Dalmolin
National Science and Technology Institute for Children’s Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre 90035-003, RS, Brazil
Marcelo A. C. Fernandes
National Science and Technology Institute for Children’s Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre 90035-003, RS, Brazil
Carolina Nör
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Vijay Ramaswamy
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Caroline Brunetto de Farias
Children’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, Brazil
André Tesainer Brunetto
Children’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, Brazil
Algemir Lunardi Brunetto
Children’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, Brazil
Lauro José Gregianin
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
Mariane da Cunha Jaeger
Children’s Cancer Institute (ICI), Porto Alegre 90620-110, RS, Brazil
Michael D. Taylor
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
Rafael Roesler
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre 90035-003, RS, Brazil
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.
