Epigenetic alterations are a fundamental aspect of cancer cells, and epigenetic drugs are currently used in clinical practice for hematological malignancies. Pediatric neuro-ectodermal tumors originate from neural crest cells and show epigenetic defects of apoptotic pathways, which points to sensitivity towards epigenetic drugs in this patient group. The young age of these patients is accompanied by However, ongoing developmental processes regulated by epigenetic mechanisms may be deregulated by epigenetic drugs in this patient group that is characterized by young age. This prompted us to study molecular effects and side-effects of low dosage epigenetic drugs in neuro-ectodermal tumor cell lines of pediatric origin. Short term combination treatment of 5-aza-2`-deoxicytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages reduced proliferation, induced wide-spread demethylating effects in 17 NBL and 5 PNET cell lines, and was accompanied by large effects on gene-expression profiles. Approximately half of the genes that were significantly upregulated upon treatment demonstrated significant demethylating effects in their promoter regions. In NBL cell lines, almost every cellular pathway (193/200) investigated demonstrated altered expression upon treatment, and resulted in upregulation of known epigenetically regulated genes such as X-chromosomal, tissue-specific, and a limited number of imprinted genes, but also known tumor suppressor genes and oncogenes. In conclusion, genome-wide methylation and gene expression changes are induced DAC and TSA treatment at nanomolar dosages. This treatment affected more than 97% of cellular pathways investigated and further studies towards the effectiveness and side-effects of epigenetic drugs are desirable in pediatric tumors. Epigenetic alterations are a fundamental aspect of cancer cells, and epigenetic drugs are currently used in clinical practice for hematological malignancies. Pediatric neuro-ectodermal tumors originate from neural crest cells and show epigenetic defects of apoptotic pathways, which points to sensitivity towards epigenetic drugs in this patient group. The young age of these patients is accompanied by However, ongoing developmental processes regulated by epigenetic mechanisms may be deregulated by epigenetic drugs in this patient group that is characterized by young age. This prompted us to study molecular effects and side-effects of low dosage epigenetic drugs in neuro-ectodermal tumor cell lines of pediatric origin. Short term combination treatment of 5-aza-2`-deoxicytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages reduced proliferation, induced wide-spread demethylating effects in 17 NBL and 5 PNET cell lines, and was accompanied by large effects on gene-expression profiles. Approximately half of the genes that were significantly upregulated upon treatment demonstrated significant demethylating effects in their promoter regions. In NBL cell lines, almost every cellular pathway (193/200) investigated demonstrated altered expression upon treatment, and resulted in upregulation of known epigenetically regulated genes such as X-chromosomal, tissue-specific, and a limited number of imprinted genes, but also known tumor suppressor genes and oncogenes. In conclusion, genome-wide methylation and gene expression changes are induced DAC and TSA treatment at nanomolar dosages. This treatment affected more than 97% of cellular pathways investigated and further studies towards the effectiveness and side-effects of epigenetic drugs are desirable in pediatric tumors.
Overall design: DNA methylation analysis of neuro-ectodermal cell lines with and without DAC and TSA
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