title: The DNA methyltransferase inhibitor zebularine exerts antitumor effects and reveals BATF2 as a poor prognostic marker for childhood medulloblastoma.
abstract: Medulloblastoma (MB) is the most common solid tumor among pediatric patients and corresponds to 20 % of all pediatric intracranial tumors in this age group. Its treatment currently involves significant side effects. Epigenetic changes such as DNA methylation may contribute to its development and progression. DNA methyltransferase (DNMT) inhibitors have shown promising anticancer effects. The agent Zebularine acts as an inhibitor of DNA methylation and shows low toxicity and high efficacy, being a promising adjuvant agent for anti-cancer chemotherapy. Several studies have reported its effects on different types of tumors; however, there are no studies reporting its effects on MB. We analyzed its potential anticancer effects in four pediatric MB cell lines. The treatment inhibited proliferation and clonogenicity, increased the apoptosis rate and the number of cells in the S phase (p < 0.05), as well as the expression of p53, p21, and Bax, and decreased cyclin A, Survivin and Bcl-2 proteins. In addition, the combination of zebularine with the chemotherapeutic agents vincristine and cisplatin resulted in synergism and antagonism, respectively. Zebularine also modulated the activation of the SHH pathway, reducing SMO and GLI1 levels and one of its targets, PTCH1, without changing SUFU levels. A microarray analysis revealed different pathways modulated by the drug, including the Toll-Like Receptor pathway and high levels of the BATF2 gene. The low expression of this gene was associated with a worse prognosis in MB. Taken together, these data suggest that Zebularine may be a potential drug for further in vivo studies of MB treatment.
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Avenida Bandeirantes 3900, 14048-900, Ribeirão Preto, SP, Brazil. augustofaria@usp.br.
authors: Augusto Faria
authors: AF
authors: Andrade
authors: Department of Pediatrics - Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil.
authors: Kleiton Silva
authors: KS
authors: Borges
authors: Department of Pediatrics - Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil.
authors: Veridiana Kiill
authors: VK
authors: Suazo
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Avenida Bandeirantes 3900, 14048-900, Ribeirão Preto, SP, Brazil.
authors: Lenisa
authors: L
authors: Geron
authors: Department of Pediatrics - Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil.
authors: Carolina Alves Pereira
authors: CA
authors: Corrêa
authors: Department of Pediatrics - Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil.
authors: Angel Mauricio
authors: AM
authors: Castro-Gamero
authors: Department of Biochemistry, Chemistry Institute, USP, São Paulo, Brazil.
authors: Elton José Rosas
authors: EJ
authors: de Vasconcelos
authors: Department of Surgery and Anatomy, Ribeirão Preto Medical School, USP, São Paulo, Brazil.
authors: Ricardo Santos
authors: RS
authors: de Oliveira
authors: Department of Pathology, Ribeirão Preto Medical School, USP, São Paulo, Brazil.
authors: Luciano
authors: L
authors: Neder
authors: Centro Infantil Boldrini & FCM/Unicamp, Campinas, Brazil.
authors: José Andres
authors: JA
authors: Yunes
authors: Centro Infantil Boldrini & FCM/Unicamp, Campinas, Brazil.
authors: Simone
authors: S
authors: Dos Santos Aguiar
authors: Department of Pediatrics - Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil.
authors: Carlos Alberto
authors: CA
authors: Scrideli
authors: Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Avenida Bandeirantes 3900, 14048-900, Ribeirão Preto, SP, Brazil.|Department of Pediatrics - Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil.
authors: Luiz Gonzaga
authors: LG
authors: Tone
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014750:Vincristine / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D050976:Basic-Leucine Zipper Transcription Factors; C569485:Batf2 protein, human; D015415:Biomarkers; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D003562:Cytidine; D014750:Vincristine; C009131:pyrimidin-2-one beta-ribofuranoside; D015254:DNA Modification Methylases; D002945:Cisplatin
keywords: DNA methyltransferases; Epigenetics; Medulloblastoma; Zebularine