Epigenetic drug combination induces genome-wide demethylation and altered gene expression in neuro-ectodermal...

Area of Science:

• Cancer epigenetics
• Pediatric oncology
• Molecular biology

Background:

• Epigenetic alterations are a hallmark of cancer, with epigenetic drugs currently used mainly for hematological malignancies.
• Pediatric neuro-ectodermal tumors, originating from neural crest cells, display epigenetic changes in pathways like apoptosis, suggesting potential sensitivity to epigenetic drugs.

Purpose of the Study:

• To investigate the molecular and functional effects of low-dose epigenetic drugs on pediatric neuro-ectodermal tumor cell lines.
• To assess the impact of epigenetic drug combinations on tumor cell proliferation and gene expression profiles.

Main Methods:

• Treatment of 17 neuroblastoma (NBL) and 5 peripheral primitive neuro-ectodermal tumor (PNET) cell lines with a combination of 5-aza-2 -deoxycytidine (DAC) and Trichostatin A (TSA) at nanomolar dosages.
• Analysis of proliferation rates, DNA demethylation, and gene expression profiles, including promoter region analysis and pathway-specific gene expression.

Main Results:

• Combination treatment with DAC and TSA at nanomolar dosages reduced proliferation in NBL and PNET cell lines.
• Widespread DNA demethylation and significant changes in gene expression profiles were observed, with approximately half of upregulated genes showing promoter demethylation.
• Marked upregulation of genes in the p53 pathway and other epigenetically regulated genes, including tumor suppressors and oncogenes, were noted in NBL cell lines.

Conclusions:

• Nanomolar dosages of DAC and TSA exert a dramatic impact on the genomes of pediatric neuro-ectodermal tumor-derived cell lines.
• These epigenetic drugs induce significant alterations in DNA methylation and concomitant changes in gene expression, highlighting their therapeutic potential.