Epigenetic mechanisms underlying arsenic-associated lung carcinogenesis

Simone G. J. van Breda*, Sandra M. H. Claessen, Ken Lo, Marcel van Herwijnen, Karen J. J. Brauers, Sofia Lisanti, Daniël H.J. Theunissen, Danyel G. J. Jennen, Stan Gaj, Theodorus de Kok, Jos C. S. Kleinjans

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Web of Science)

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 A mu M), intermediate (0.4 A mu M) and high (2 A mu M) 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.
Original languageEnglish
Pages (from-to)1959-1969
JournalArchives of Toxicology
Volume89
Issue number11
DOIs
Publication statusPublished - Nov 2015

Keywords

  • Epigenomics
  • Transcriptomics
  • Arsenic
  • Lung cancer
  • Genetic pathways
  • Data integration

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