title: Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma.
abstract: Epigenetic aberrations and a CpG island methylator phenotype are associated with poor outcome in children with neuroblastoma (NB). Previously, we have shown that valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, exerts antitumor effects in an NB xenograft model. However, the underlying antitumor molecular mechanisms are largely unknown. In this study, we examined the role of HDAC in cell proliferation, cell cycle progression, gene expression patterns, and epigenome in NB. Cell proliferation, cell cycle progression, caspase activity, RNA and protein expression, quantitative methylation, and global DNA methylation were examined in NBL-W-N and LA1-55n NB cell lines. Our studies showed that inhibition of HDAC decreased NB proliferation, and induced caspase activity and G1 growth arrest. Expression patterns of cancer-related genes were modulated by VPA. The expression of THBS1, CASP8, SPARC, CDKN1A, HIC1, CDKN1B, and HIN1 was upregulated, and that of MYCN and TIG1 was downregulated. HDAC inhibition decreased methylation levels of THBS1 and RASSF1A promoters. Inhibition of HDAC increased acetylation of histone 4 and overall DNA methylation levels. Our studies showed that inhibition of HDAC blocked cell proliferation and cell cycle progression in relation to alteration in cancer-related genes, increased overall DNA methylation, and decreased methylation of tumor suppressor genes. Further studies examining the antitumor effects of VPA in NB are warranted.
authors.affiliation: Department of Pediatric Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University, School of Medicine, Shanghai, People's Republic of China.
authors.forename: Song
authors.initials: S
authors.lastname: Gu
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.forename: Alexandre
authors.initials: A
authors.lastname: Chlenski
authors.forename: Helen R
authors.initials: HR
authors.lastname: Salwen
authors.forename: Ziyan
authors.initials: Z
authors.lastname: Lu
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid; D006655:Histone Deacetylases