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 language | English (US) |
|---|---|
| Pages (from-to) | 1054-1066 |
| Number of pages | 13 |
| Journal | Anti-Cancer Drugs |
| Volume | 23 |
| Issue number | 10 |
| DOIs | |
| State | Published - Nov 1 2012 |
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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
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 journal › Article
}
TY - JOUR
T1 - Valproic acid shows a potent antitumor effect with alteration of DNA methylation in neuroblastoma
AU - Gu, Song
AU - Tian, Yufeng
AU - Chlenski, Alexandre
AU - Salwen, Helen R.
AU - Lu, Ziyan
AU - Raj, J. Usha
AU - Yang, Qiwei
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
KW - DNA methylation
KW - cell cycle
KW - cell proliferation
KW - histone acetylation
KW - histone deacetylase
KW - neuroblastoma
KW - valproic acid
UR - http://www.scopus.com/inward/record.url?scp=84867580617&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867580617&partnerID=8YFLogxK
U2 - 10.1097/CAD.0b013e32835739dd
DO - 10.1097/CAD.0b013e32835739dd
M3 - Article
VL - 23
SP - 1054
EP - 1066
JO - Anti-Cancer Drugs
JF - Anti-Cancer Drugs
SN - 0959-4973
IS - 10
ER -