Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma

Song Gu, Yufeng Tian, Alexandre Chlenski, Helen R. Salwen, Ziyan Lu, J. Usha Raj, Qiwei Yang

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1054-1066
Number of pages13
JournalAnti-Cancer Drugs
Volume23
Issue number10
DOIs
StatePublished - Nov 1 2012

Fingerprint

Valproic Acid
DNA Methylation
Histone Deacetylases
Neuroblastoma
Methylation
Neoplasm Genes
Cell Proliferation
Caspases
Cell Cycle
cdc Genes
CpG Islands
Histone Deacetylase Inhibitors
Acetylation
Tumor Suppressor Genes
Heterografts
Epigenomics
Histones
Down-Regulation
RNA
Phenotype

Keywords

  • DNA methylation
  • cell cycle
  • cell proliferation
  • histone acetylation
  • histone deacetylase
  • neuroblastoma
  • valproic acid

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

Cite this

Gu, S., Tian, Y., Chlenski, A., Salwen, H. R., Lu, Z., Raj, J. U., & Yang, Q. (2012). Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. Anti-Cancer Drugs, 23(10), 1054-1066. https://doi.org/10.1097/CAD.0b013e32835739dd

Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. / Gu, Song; Tian, Yufeng; Chlenski, Alexandre; Salwen, Helen R.; Lu, Ziyan; Raj, J. Usha; Yang, Qiwei.

In: Anti-Cancer Drugs, Vol. 23, No. 10, 01.11.2012, p. 1054-1066.

Research output: Contribution to journalArticle

Gu, S, Tian, Y, Chlenski, A, Salwen, HR, Lu, Z, Raj, JU & Yang, Q 2012, 'Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma', Anti-Cancer Drugs, vol. 23, no. 10, pp. 1054-1066. https://doi.org/10.1097/CAD.0b013e32835739dd
Gu, Song ; Tian, Yufeng ; Chlenski, Alexandre ; Salwen, Helen R. ; Lu, Ziyan ; Raj, J. Usha ; Yang, Qiwei. / Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma. In: Anti-Cancer Drugs. 2012 ; Vol. 23, No. 10. pp. 1054-1066.
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