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| Status |
Public on Jul 01, 2012 |
| Title |
Nanomolar treatment with epigenetic drug combination induces genome-wide methylation and expression alterations in neuro-ectodermal cell lines [mRNA] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Abstract: 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 makes the introduction of epigenetic drugs in this patient category logical. However, the young age of these patients is accompanied by ongoing developmental processes which are regulated epigenetic mechanisms, and prompted us to study molecular effects of nanomolar dosage epigenetic drugs in neuro-ectodermal tumor cell lines. Combination treatment of 5-aza-2`-deoxicytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages resulted in wide-spread demethylating effects in 17 NBL and 5 PNET cell lines in vitro. This widespread demethylation had large effects on gene-expression profiles. 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 few imprinted genes. Integration analysis of CpG island methylation array data and whole genome gene expression data identified 30 genes potentially upregulated by gene promoter demethylation. Homeobox genes frequently showed demethylation in both short term (72 hours) and long term cultures (3 months) of NBL lines. Continuous treatment with epigenetic drugs resulted in low rates of proliferation. The low rate of proliferation that might explain limited consecutive demethylation upon prolonged exposure. In conclusion, genome-wide methylation and gene expression changes are induced DAC and TSA treatment at nanomolar dosages. These effects affected more than 97% of cellular pathways investigated. Further studies towards the effects of epigenetic drug combinations are advised before being applied in clinical trials for pediatric patients.
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| Overall design |
Comparison of gene expression profiles of neuro-ectodermal cell lines with and without DAC and TSA
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| Citation(s) |
23864224 |
| Submission date |
Jan 19, 2012 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Floor Duijkers |
| Organization name |
Erasmus MC
|
| Department |
Pediatric Oncology-Hematology
|
| Street address |
Dr. Molewaterplein 50-60 Ee15-02
|
| City |
Rotterdam |
| ZIP/Postal code |
3015 GE |
| Country |
Netherlands |
| |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
|
| Samples (44)
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| This SubSeries is part of SuperSeries: |
| GSE35798 |
Nanomolar treatment with epigenetic drug combination induces genome-wide methylation and expression alterations in neuro-ectodermal cell lines |
|
| Relations |
| BioProject |
PRJNA155955 |
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