Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment.

Julia Krushkal,Yingdong Zhao,Anne Monks,James H Doroshow,Curtis Hose,Richard Simon

doi:10.1186/s13148-016-0240-3

Abstract

BackgroundAberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Genetic components of the folate-mediated one-carbon metabolism pathway can affect DNA methylation and other vital cell functions, including DNA synthesis, amino acid biosynthesis, and cell growth.ResultsWe used a bioinformatics tool, the Transcriptional Pharmacology Workbench, to analyze temporal changes in gene expression among epigenetic regulators of DNA methylation and demethylation, and one-carbon metabolism genes in response to cancer drug treatment. We analyzed gene expression information from the NCI-60 cancer cell line panel after treatment with five antitumor agents, 5-azacytidine, doxorubicin, vorinostat, paclitaxel, and cisplatin. Each antitumor agent elicited concerted changes in gene expression of multiple pathway components across the cell lines. Expression changes of FOLR2, SMUG1, GART, GADD45A, MBD1, MTR, MTHFD1, and CTH were significantly correlated with chemosensitivity to some of the agents. Among many genes with concerted expression response to individual antitumor agents were genes encoding DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, epigenetic and DNA repair factors MGMT, GADD45A, and MBD1, and one-carbon metabolism pathway members MTHFD1, TYMS, DHFR, MTR, MAT2A, SLC19A1, ATIC, and GART.ConclusionsThese transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0240-3) contains supplementary material, which is available to authorized users.

Highlights

Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment
Additional molecular factors include methyl-CpG-binding domain proteins (MBDs), proliferating cell nuclear antigen (PCNA), herpes virus-associated ubiquitin specific protease USP7, single-strand-selective monofunctional uracil-DNA glycosylase (SMUG1), and DNA methyltransferase 3-like protein (DNMT3L) that act as interaction partners of proteins involved in DNA methylation or demethylation, and NADP+-dependent isocitrate dehydrogenases (IDH1 and IDH2) that produce metabolites which interfere with TETmediated DNA demethylation [6, 9,10,11,12,13]
Our results suggest that despite a high level of genetic and cancer type heterogeneity among different tumor cell lines in the NCI-60 panel, multiple genes encoding epigenetic factors and members of the one-carbon metabolism (OCM) pathway exhibited expression changes in the same direction across most of the cell lines in response to several cancer drugs analyzed in this study

Summary

Introduction

Aberrant patterns of DNA methylation are abundant in cancer, and epigenetic pathways are increasingly being targeted in cancer drug treatment. Levels and locus-specific patterns of DNA methylation are affected by a complex network of interactions among molecular factors (Additional file 1: Table S1). They include proteins directly involved in DNA methylation, e.g., DNA 5′ cytosine-methyltransferases or DNMTs (DNMT1, DNMT3A, and DNMT3B) and DNA hydroxymethylation and demethylation, such as ten-eleven translocation methylcytosine dioxygenases (TET1, TET2, and TET3), activation-induced cytidine deaminase (AICDA or AID), apolipoprotein B mRNA editing activity DNA deaminases (APOBEC1, APOBEC2, APOBEC3A, and APOBEC3C), thymine-DNA glycosylase (TDG), and demethylating DNA repair factors (O6-methylguanineDNA-methyltransferase, or MGMT, and growth arrest and DNA damage 45 protein A, or GADD45A) [6,7,8]. Additional molecular factors include methyl-CpG-binding domain proteins (MBDs), proliferating cell nuclear antigen (PCNA), herpes virus-associated ubiquitin specific protease USP7, single-strand-selective monofunctional uracil-DNA glycosylase (SMUG1), and DNA methyltransferase 3-like protein (DNMT3L) that act as interaction partners of proteins involved in DNA methylation or demethylation, and NADP+-dependent isocitrate dehydrogenases (IDH1 and IDH2) that produce metabolites which interfere with TETmediated DNA demethylation [6, 9,10,11,12,13]

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