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Epigenetic mechanisms underlying arsenic-associated lung carcinogenesis

Lookup NU author(s): Sofia Lisanti

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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.

Publication metadata

Author(s): van Breda SGJ, Claessen SMH, Lo K, van Herwijnen M, Brauers KJJ, Lisanti S, Theunissen DHJ, Jennen DGJ, Gaj S, de Kok TMCM, Kleinjans JCS

Publication type: Article

Publication status: Published

Journal: Archives of Toxicology

Year: 2015

Volume: 89

Issue: 11

Pages: 1959-1969

Print publication date: 01/11/2015

Online publication date: 09/09/2014

Acceptance date: 25/08/2014

ISSN (print): 0340-5761

ISSN (electronic): 1432-0738

Publisher: Springer Berlin Heidelberg

URL: http://dx.doi.org/10.1007/s00204-014-1351-2

DOI: 10.1007/s00204-014-1351-2

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