Document Detail


Chromatin remodelling at the topoisomerase II-beta promoter is associated with enhanced sensitivity to etoposide in human neuroblastoma cell lines.
MedLine Citation:
PMID:  20886683     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Chandra M Das; Peter E Zage; Pete Taylor; Dolly Aguilera; Johannes E A Wolff; Dean Lee; Vidya Gopalakrishnan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  European journal of cancer (Oxford, England : 1990)     Volume:  46     ISSN:  1879-0852     ISO Abbreviation:  Eur. J. Cancer     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-30     Completed Date:  2011-01-19     Revised Date:  2013-08-27    
Medline Journal Info:
Nlm Unique ID:  9005373     Medline TA:  Eur J Cancer     Country:  England    
Other Details:
Languages:  eng     Pagination:  2771-80     Citation Subset:  IM    
Affiliation:
Division of Pediatrics, Children’s Cancer Hospital, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / therapeutic use*
Cell Cycle
Cell Line, Tumor
Cell Survival
Chromatin Assembly and Disassembly / drug effects*
Chromatin Immunoprecipitation
DNA Topoisomerases, Type II / genetics,  metabolism*
DNA-Binding Proteins / genetics,  metabolism*
Drug Synergism
Epigenomics
Etoposide / therapeutic use*
Histone Deacetylase Inhibitors / therapeutic use
Humans
Inhibitory Concentration 50
Neuroblastoma / drug therapy*,  enzymology
Valproic Acid / therapeutic use*
Grant Support
ID/Acronym/Agency:
P50 CA127001/CA/NCI NIH HHS; P50 CA127001-02/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/DNA-Binding Proteins; 0/Histone Deacetylase Inhibitors; 33419-42-0/Etoposide; 99-66-1/Valproic Acid; EC 5.99.1.3/DNA Topoisomerases, Type II; EC 5.99.1.3/DNA topoisomerase II beta
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