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

Autor:	Freire NH; Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Herlinger AL; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Vanini J; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Dalmolin M; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil.; InovAI Lab, nPITI/IMD, Federal University of Rio Grande do Norte, Natal, RN, Brazil.; Bioinformatics Multidisciplinary Environment (BioME), Federal University of Rio Grande do Norte, Natal, RN, Brazil., Fernandes MAC; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil.; InovAI Lab, nPITI/IMD, Federal University of Rio Grande do Norte, Natal, RN, Brazil.; Bioinformatics Multidisciplinary Environment (BioME), Federal University of Rio Grande do Norte, Natal, RN, Brazil.; Department of Computer Engineering and Automation, Federal University of Rio Grande do Norte, Natal, RN, Brazil., Nör C; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada., Ramaswamy V; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., de Farias CB; Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Brunetto AT; Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Brunetto AL; Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Gregianin LJ; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil.; Department of Pediatrics, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; Pediatric Oncology Service, Clinical Hospital, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil., da Cunha Jaeger M; Children's Cancer Institute (ICI), Porto Alegre, RS, Brazil.; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil., Taylor MD; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.; Department of Surgery, University of Toronto, Toronto, ON, Canada.; Texas Children's Cancer and Hematology Center, Houston, TX, USA.; Department of Pediatrics - Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.; Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.; Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.; Hematology-Oncology Section, Texas Children's Cancer Center, Houston, TX, USA., Roesler R; Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.; National Science and Technology Institute for Children's Cancer Biology and Pediatric Oncology-INCT BioOncoPed, Porto Alegre, RS, Brazil.; Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 25. Date of Electronic Publication: 2024 Sep 25.
DOI:	10.1101/2024.09.23.614476
Abstrakt:	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 spheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and increased expression of differentiation marker genes TUBB3 and ENO2 . 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 genes regulated by VPA, stemness regulators MYC and NES showed 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 modulation of stemness, neuronal differentiation, and 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 expression of MYC and increase in TP53 . Competing Interests: Conflict of Interest The authors declare no competing interests.
Databáze:	MEDLINE
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