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01-10-2013 | Original Paper

Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines

Authors: Floor A.M. Duijkers, Renee X. de Menezes, Inès J. Goossens-Beumer, Dominique J.P.M. Stumpel, Pieter Admiraal, Rob Pieters, Jules P.P. Meijerink, Max M. van Noesel

Published in: Cellular Oncology | Issue 5/2013

Abstract

Background

Epigenetic alterations are inherent to cancer cells, and epigenetic drugs are currently primarily used to treat hematological malignancies. Pediatric neuro-ectodermal tumors originate from neural crest cells and also exhibit epigenetic alterations involving e.g. apoptotic pathways, which suggests that these tumors may also be sensitive to epigenetic drugs. This notion prompted us to assess molecular and functional effects of low dosage epigenetic drugs in neuro-ectodermal tumor-derived cell lines of pediatric origin.

Results

In 17 neuroblastoma (NBL) and 5 peripheral primitive neuro-ectodermal tumor (PNET) cell lines a combination treatment of 5-aza-2′-deoxycytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages was found to reduce proliferation and to induce wide-spread DNA demethylation, accompanied by major changes in gene expression profiles. Approximately half of the genes that were significantly up-regulated upon treatment exhibited a significant demethylation in their promoter regions. In the NBL cell lines, almost every cellular pathway (193/200) investigated showed expression alterations after treatment, especially a marked up-regulation of genes in the p53 pathway. The combination treatment also resulted in up-regulation of known epigenetically regulated genes such as X-chromosomal genes, tissue-specific genes and a limited number of imprinted genes, as well as known tumor suppressor genes and oncogenes.

Conclusions

Nanomolar dosages of epigenetic drugs have a dramatic impact on the genomes of neuro-ectodermal tumor-derived cell lines, including alterations in DNA methylation and concomitant alterations in gene expression.

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Title: Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal tumor-derived cell lines
Authors: Floor A.M. Duijkers
Renee X. de Menezes
Inès J. Goossens-Beumer
Dominique J.P.M. Stumpel
Pieter Admiraal
Rob Pieters
Jules P.P. Meijerink
Max M. van Noesel
Publication date: 01-10-2013
Publisher: Springer Netherlands
Published in: Cellular Oncology / Issue 5/2013
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-013-0140-x

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