title: 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.
abstract: BACKGROUND
  Aberrant 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850 USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Krushkal
authors.affiliation: Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850 USA.
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Hose
authors.affiliation: Molecular Pharmacology Group, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702 USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Monks
authors.affiliation: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892 USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Dr., Rockville, MD 20850 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Simon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019295:Computational Biology / Q000379:methods*; D019175:DNA Methylation / Q000187:drug effects*; D004317:Doxorubicin / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005492:Folic Acid / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D000077337:Vorinostat; D004317:Doxorubicin; D005492:Folic Acid; D001374:Azacitidine; D017239:Paclitaxel; D002945:Cisplatin
keywords: Cancer drug treatment; DNA methylation; Epigenetic analysis; Folate metabolism; Gene expression; NCI-60 cell lines