title: Epigenetic mechanisms underlying arsenic-associated lung carcinogenesis.
abstract: Arsenic is an established human carcinogen, but the mechanisms through which it contributes to for instance lung cancer development are still unclear. As arsenic is methylated during its metabolism, it may interfere with the DNA methylation process, and is therefore considered to be an epigenetic carcinogen. In the present study, we hypothesize that arsenic is able to induce DNA methylation changes, which lead to changes in specific gene expression, in pathways associated with lung cancer promotion and progression. A549 human adenocarcinoma lung cells were exposed to a low (0.08 µM), intermediate (0.4 µM) and high (2 µM) concentration of sodium arsenite for 1, 2 and 8 weeks. DNA was isolated for whole-genome DNA methylation analyses using NimbleGen 2.1 M deluxe promoter arrays. In addition, RNA was isolated for whole-genome transcriptomic analysis using Affymetrix microarrays. Arsenic modulated DNA methylation and expression levels of hundreds of genes in a dose-dependent and time-dependent manner. By combining whole-genome DNA methylation and gene expression data with possibly involved transcription factors, a large molecular interaction network was created based on transcription factor-target gene pairs, consisting of 216 genes. A tumor protein p53 (TP53) subnetwork was identified, showing the interactions of TP53 with other genes affected by arsenic. Furthermore, multiple other new genes were discovered showing altered DNA methylation and gene expression. In particular, arsenic modulated genes which function as transcription factor, thereby affecting target genes which are known to play a role in lung cancer promotion and progression.
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. s.vanbreda@maastrichtuniversity.nl.
authors.forename: Simone G J
authors.initials: SG
authors.lastname: van Breda
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Sandra M H
authors.initials: SM
authors.lastname: Claessen
authors.affiliation: Roche Applied Science, Madison, WI, 53719, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Lo
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: van Herwijnen
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Karen J J
authors.initials: KJ
authors.lastname: Brauers
authors.affiliation: Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Lisanti
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Daniël H J
authors.initials: DH
authors.lastname: Theunissen
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Danyel G J
authors.initials: DG
authors.lastname: Jennen
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Stan
authors.initials: S
authors.lastname: Gaj
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Theo M C M
authors.initials: TM
authors.lastname: de Kok
authors.affiliation: Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018053:Arsenites; D002273:Carcinogens; D017670:Sodium Compounds; D016159:Tumor Suppressor Protein p53; C017947:sodium arsenite
keywords: Arsenic; Data integration; Epigenomics; Genetic pathways; Lung cancer; Transcriptomics