ABSTRACT
OBJECTIVE: This study investigated epigenetic modifications in human central nervous system atypical teratoid rhabdoid tumors (AT/RTs), in response to inhibition of insulin-like growth factor receptor 1 (IGF-1R). MATERIALS AND METHODS: Tumor tissue was obtained from two pediatric patients, tissue was dissociated, and primary cultures were established. Cultured cells were treated with picropodophyllin (PPP; 0, 1, and 2 µM for 48 h), a selective IGF-1R inhibitor. Histone acetylation and methylation patterns (H3K9ac, H3K18ac, H3K4me3, H3K27me3) and levels of histone deacetylases (HDACs; HDAC1, HDAC3, and SirT1) and histone acetyl transferases (GCN5 and p300) were examined. H3K9ac and H3K18ac decreased in response to treatment with PPP. HDAC levels showed a biphasic response, increasing with 1 µM PPP, but then decreasing with 2 µM PPP. CONCLUSION: Inhibition of IGF-1R modified epigenetic status in AT/RT. Determining the mechanisms behind these modifications will guide the development of novel therapeutic targets for this malignant embryonal cancer.
Subject(s)
Central Nervous System Neoplasms/pathology , Epigenesis, Genetic/physiology , Epigenomics , Receptor, IGF Type 1/metabolism , Rhabdoid Tumor/pathology , Signal Transduction/drug effects , Teratoma/pathology , Acetylation/drug effects , Dose-Response Relationship, Drug , Epigenesis, Genetic/drug effects , Histone Acetyltransferases/metabolism , Histone Deacetylases/metabolism , Histones/metabolism , Humans , Methylation/drug effects , Podophyllotoxin/analogs & derivatives , Podophyllotoxin/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/genetics , Tumor Cells, Cultured/drug effectsABSTRACT
Maternal folic acid (FA) intake has beneficial effects in preventing neural tube defects and may also play a role in the prevention of adult onset diseases such as Alzheimer's disease, dementia, neuropsychiatric disorders, cardiovascular diseases, and cerebral ischemia. This review will focus on the effects of maternal FA intake on neural crest stem cell proliferation and differentiation. Although FA is generally considered beneficial, it has the potential of promoting cell proliferation at the expense of differentiation. In some situations, this may lead to miscarriage or postnatal developmental abnormalities. Therefore, a blind approach such as "FA for everyone" is not necessarily the best course of action. Ultimately, the best approach for FA supplementation, and potentially other nutritional supplements, will include customized patient genomic profiles for determining dose and duration.