Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

Julia E. Rager, Sloane K. Tilley, Samantha E. Tulenko, Lisa Smeester, Paul D. Ray, Andrew Yosim, Jenna M. Currier, María C. Ishida, Maria Del Carmen González-Horta, Blanca Sánchez-Ramírez, Lourdes Ballinas-Casarrubias, Daniela S. Gutiérrez-Torres, Zuzana Drobná, Luz M. Del Razo, Gonzalo G. García-Vargas, William Y. Kim, Yi Hui Zhou, Fred A. Wright, Miroslav Stýblo, Rebecca C. Fry

Research output: Research - peer-reviewArticle

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Abstract

There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer.

LanguageEnglish (US)
Pages1144-1155
Number of pages12
JournalChemical Research in Toxicology
Volume28
Issue number6
DOIs
StatePublished - Jun 15 2015

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Arsenic
DNA Methylation
Urinary Bladder Neoplasms
Genes
Methylation
Carcinogenesis
Genome
Neoplasms
Atlases
Neoplasm Genes
Metabolic Diseases
Mexico
Urinary Bladder
Transcription Factors
Binding Sites
Health
Metabolites
Tissue

ASJC Scopus subject areas

  • Toxicology

Cite this

Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer. / Rager, Julia E.; Tilley, Sloane K.; Tulenko, Samantha E.; Smeester, Lisa; Ray, Paul D.; Yosim, Andrew; Currier, Jenna M.; Ishida, María C.; González-Horta, Maria Del Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Gutiérrez-Torres, Daniela S.; Drobná, Zuzana; Del Razo, Luz M.; García-Vargas, Gonzalo G.; Kim, William Y.; Zhou, Yi Hui; Wright, Fred A.; Stýblo, Miroslav; Fry, Rebecca C.

In: Chemical Research in Toxicology, Vol. 28, No. 6, 15.06.2015, p. 1144-1155.

Research output: Research - peer-reviewArticle

Rager, JE, Tilley, SK, Tulenko, SE, Smeester, L, Ray, PD, Yosim, A, Currier, JM, Ishida, MC, González-Horta, MDC, Sánchez-Ramírez, B, Ballinas-Casarrubias, L, Gutiérrez-Torres, DS, Drobná, Z, Del Razo, LM, García-Vargas, GG, Kim, WY, Zhou, YH, Wright, FA, Stýblo, M & Fry, RC 2015, 'Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer' Chemical Research in Toxicology, vol 28, no. 6, pp. 1144-1155. DOI: 10.1021/tx500393y
Rager, Julia E. ; Tilley, Sloane K. ; Tulenko, Samantha E. ; Smeester, Lisa ; Ray, Paul D. ; Yosim, Andrew ; Currier, Jenna M. ; Ishida, María C. ; González-Horta, Maria Del Carmen ; Sánchez-Ramírez, Blanca ; Ballinas-Casarrubias, Lourdes ; Gutiérrez-Torres, Daniela S. ; Drobná, Zuzana ; Del Razo, Luz M. ; García-Vargas, Gonzalo G. ; Kim, William Y. ; Zhou, Yi Hui ; Wright, Fred A. ; Stýblo, Miroslav ; Fry, Rebecca C./ Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer. In: Chemical Research in Toxicology. 2015 ; Vol. 28, No. 6. pp. 1144-1155
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abstract = "There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer.",
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T1 - Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

AU - Rager,Julia E.

AU - Tilley,Sloane K.

AU - Tulenko,Samantha E.

AU - Smeester,Lisa

AU - Ray,Paul D.

AU - Yosim,Andrew

AU - Currier,Jenna M.

AU - Ishida,María C.

AU - González-Horta,Maria Del Carmen

AU - Sánchez-Ramírez,Blanca

AU - Ballinas-Casarrubias,Lourdes

AU - Gutiérrez-Torres,Daniela S.

AU - Drobná,Zuzana

AU - Del Razo,Luz M.

AU - García-Vargas,Gonzalo G.

AU - Kim,William Y.

AU - Zhou,Yi Hui

AU - Wright,Fred A.

AU - Stýblo,Miroslav

AU - Fry,Rebecca C.

PY - 2015/6/15

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N2 - There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer.

AB - There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer.

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