Chromatin remodelling at the topoisomerase II-beta promoter is associated with enhanced sensitivity to etoposide in human neuroblastoma cell lines

Abstract Etoposide, an inhibitor of topoisomerase II, promotes DNA damage and apoptosis of cancer cells and is a component of standard therapy for neuroblastoma. Resistance to etoposide has been observed in neural tumour cells expressing lower levels of topoisomerase II. In the present study, we hav...

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Bibliographic Details
Published in:European journal of cancer (1990) 2010-10, Vol.46 (15), p.2771-2780
Main Authors: Das, Chandra M, Zage, Peter E, Taylor, Pete, Aguilera, Dolly, Wolff, Johannes E.A, Lee, Dean, Gopalakrishnan, Vidya
Format: Article
Language:English
Subjects:
Acetylation
Antineoplastic Agents, Phytogenic - therapeutic use
Biological and medical sciences
Cell Cycle
Cell Line, Tumor
Cell Survival
Chromatin Assembly and Disassembly - drug effects
Chromatin Immunoprecipitation
DNA Topoisomerases, Type II - genetics
DNA Topoisomerases, Type II - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Drug Synergism
Epigenomics
Etoposide
Etoposide - therapeutic use
Hematology, Oncology and Palliative Medicine
Histone deacetylase inhibitor
Histone Deacetylase Inhibitors - therapeutic use
Humans
Inhibitory Concentration 50
Medical sciences
Neuroblastoma
Neuroblastoma - drug therapy
Neuroblastoma - enzymology
Pharmacology. Drug treatments
Topoisomerase
Tumors
Valproic acid
Valproic Acid - therapeutic use
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Summary:Abstract Etoposide, an inhibitor of topoisomerase II, promotes DNA damage and apoptosis of cancer cells and is a component of standard therapy for neuroblastoma. Resistance to etoposide has been observed in neural tumour cells expressing lower levels of topoisomerase II. In the present study, we have examined the contribution of epigenetic modulation of gene expression in the potentiation of etoposide-mediated cytotoxicity in neuroblastoma cells. Specifically, we studied the effects of histone deacetylase inhibition with valproic acid on topoisomerase II gene expression and apoptosis in response to etoposide. Using human neuroblastoma cell lines SK-N-AS and SK-N-SH, we show that although the combination of valproic acid and etoposide promoted a reduction in growth compared to either drug alone in both cells, the effect was substantially enhanced in SK-N-AS compared to SK-N-SH cells. An increase in histone H3 acetylation and p21 expression was observed in both cell lines, however, upregulation of topoisomerase II-beta gene expression and an increase in PARP cleavage was observed in SK-N-AS cells only. Furthermore, chromatin immunoprecipitation assays revealed an increase in acetylation of histone H3 at the cognate topoisomerase II-beta gene after treatment with valproic acid in SK-N-AS cells. These results suggest a potential epigenetic mechanism of regulation of the topoisomerase II-beta gene and a possible role for its increased expression in the sensitivity of SK-N-AS neuroblastoma cells to etoposide.
ISSN:0959-8049
1879-0852
DOI:10.1016/j.ejca.2010.05.010