Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation

Paul L. Severson; Erik J. Tokar; Lukas Vrba; Michael P. Waalkes; Bernard W. Futscher

doi:10.4161/epi.22163

Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation

Paul L. Severson, Erik J. Tokar, Lukas Vrba, Michael P. Waalkes, Bernard W. Futscher

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Epigenetic dysfunction is a known contributor in carcinogenesis, and is emerging as a mechanism involved in toxicantinduced malignant transformation for environmental carcinogens such as arsenicals or cadmium. In addition to aberrant DNA methylation of single genes, another manifestation of epigenetic dysfunction in cancer is agglomerative DNA methylation, which can participate in long-range epigenetic silencing that targets many neighboring genes and has been shown to occur in several types of clinical cancers. Using in vitro model systems of toxicant-induced malignant transformation, we found hundreds of aberrant DNA methylation events that emerge during malignant transformation, some of which occur in an agglomerative fashion. In an arsenite-transformed prostate epithelial cell line, the protocadherin (PC DH), HOXC and HOXD gene family clusters are targeted for agglomerative DNA methylation. The agglomerative DNA methylation changes induced by arsenicals appear to be common and clinically relevant events, since they occur in other human cancer cell lines and models of malignant transformation, as well as clinical cancer specimens. Aberrant DNA methylation in general occurred more often within histone H3 lysine-27 trimethylation stem cell domains. We found a striking association between enrichment of histone H3 lysine-9 trimethylation stem cell domains and toxicant-induced agglomerative DNA methylation, suggesting these epigenetic modifications may become aberrantly linked during malignant transformation. In summary, we found an association between toxicant-induced malignant transformation and agglomerative DNA methylation, which lends further support to the hypothesis that epigenetic dysfunction plays an important role in toxicant-induced malignant transformation.

Original language	English (US)
Pages (from-to)	1238-1248
Number of pages	11
Journal	Epigenetics
Volume	7
Issue number	11
DOIs	https://doi.org/10.4161/epi.22163
State	Published - Nov 2012

Keywords

Agglomerative DNA methylation
Arsenic
Cadmium
DNA methylation
Epigenetics
H3K27me3
H3K9me3
Long-range epigenetic silencing
Malignant transformation

ASJC Scopus subject areas

Molecular Biology
Cancer Research

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@article{be6f74053e5a46e5baa628f4b749841e,

title = "Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation",

abstract = "Epigenetic dysfunction is a known contributor in carcinogenesis, and is emerging as a mechanism involved in toxicantinduced malignant transformation for environmental carcinogens such as arsenicals or cadmium. In addition to aberrant DNA methylation of single genes, another manifestation of epigenetic dysfunction in cancer is agglomerative DNA methylation, which can participate in long-range epigenetic silencing that targets many neighboring genes and has been shown to occur in several types of clinical cancers. Using in vitro model systems of toxicant-induced malignant transformation, we found hundreds of aberrant DNA methylation events that emerge during malignant transformation, some of which occur in an agglomerative fashion. In an arsenite-transformed prostate epithelial cell line, the protocadherin (PC DH), HOXC and HOXD gene family clusters are targeted for agglomerative DNA methylation. The agglomerative DNA methylation changes induced by arsenicals appear to be common and clinically relevant events, since they occur in other human cancer cell lines and models of malignant transformation, as well as clinical cancer specimens. Aberrant DNA methylation in general occurred more often within histone H3 lysine-27 trimethylation stem cell domains. We found a striking association between enrichment of histone H3 lysine-9 trimethylation stem cell domains and toxicant-induced agglomerative DNA methylation, suggesting these epigenetic modifications may become aberrantly linked during malignant transformation. In summary, we found an association between toxicant-induced malignant transformation and agglomerative DNA methylation, which lends further support to the hypothesis that epigenetic dysfunction plays an important role in toxicant-induced malignant transformation.",

keywords = "Agglomerative DNA methylation, Arsenic, Cadmium, DNA methylation, Epigenetics, H3K27me3, H3K9me3, Long-range epigenetic silencing, Malignant transformation",

author = "Severson, {Paul L.} and Tokar, {Erik J.} and Lukas Vrba and Waalkes, {Michael P.} and Futscher, {Bernard W.}",

note = "Funding Information: This work was supported by the National Institutes of Health (P42 ES04940, ES006694, CA23074, 5T32ES16652-3 to P.S.). We thank the laboratory of Dr A. Jay Gandolfi for providing the URO-MSC52 and URO-MSC12+24(-) cell lines. We are grateful to the laboratory of Drs Donald and Mary Ann Sens for sharing UROtsa, URO-ASSC and URO-CDSC. We wish to thank Dr Petr Novak for contributing his time and insightful comments. The costs for publication of this article were deferred by the Southwest Environmental Health Sciences Center (ES006694). This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the US government.",

year = "2012",

month = nov,

doi = "10.4161/epi.22163",

language = "English (US)",

volume = "7",

pages = "1238--1248",

journal = "Epigenetics",

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publisher = "Landes Bioscience",

number = "11",

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T1 - Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation

AU - Severson, Paul L.

AU - Tokar, Erik J.

AU - Vrba, Lukas

AU - Waalkes, Michael P.

AU - Futscher, Bernard W.

N1 - Funding Information: This work was supported by the National Institutes of Health (P42 ES04940, ES006694, CA23074, 5T32ES16652-3 to P.S.). We thank the laboratory of Dr A. Jay Gandolfi for providing the URO-MSC52 and URO-MSC12+24(-) cell lines. We are grateful to the laboratory of Drs Donald and Mary Ann Sens for sharing UROtsa, URO-ASSC and URO-CDSC. We wish to thank Dr Petr Novak for contributing his time and insightful comments. The costs for publication of this article were deferred by the Southwest Environmental Health Sciences Center (ES006694). This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the US government.

PY - 2012/11

Y1 - 2012/11

N2 - Epigenetic dysfunction is a known contributor in carcinogenesis, and is emerging as a mechanism involved in toxicantinduced malignant transformation for environmental carcinogens such as arsenicals or cadmium. In addition to aberrant DNA methylation of single genes, another manifestation of epigenetic dysfunction in cancer is agglomerative DNA methylation, which can participate in long-range epigenetic silencing that targets many neighboring genes and has been shown to occur in several types of clinical cancers. Using in vitro model systems of toxicant-induced malignant transformation, we found hundreds of aberrant DNA methylation events that emerge during malignant transformation, some of which occur in an agglomerative fashion. In an arsenite-transformed prostate epithelial cell line, the protocadherin (PC DH), HOXC and HOXD gene family clusters are targeted for agglomerative DNA methylation. The agglomerative DNA methylation changes induced by arsenicals appear to be common and clinically relevant events, since they occur in other human cancer cell lines and models of malignant transformation, as well as clinical cancer specimens. Aberrant DNA methylation in general occurred more often within histone H3 lysine-27 trimethylation stem cell domains. We found a striking association between enrichment of histone H3 lysine-9 trimethylation stem cell domains and toxicant-induced agglomerative DNA methylation, suggesting these epigenetic modifications may become aberrantly linked during malignant transformation. In summary, we found an association between toxicant-induced malignant transformation and agglomerative DNA methylation, which lends further support to the hypothesis that epigenetic dysfunction plays an important role in toxicant-induced malignant transformation.

AB - Epigenetic dysfunction is a known contributor in carcinogenesis, and is emerging as a mechanism involved in toxicantinduced malignant transformation for environmental carcinogens such as arsenicals or cadmium. In addition to aberrant DNA methylation of single genes, another manifestation of epigenetic dysfunction in cancer is agglomerative DNA methylation, which can participate in long-range epigenetic silencing that targets many neighboring genes and has been shown to occur in several types of clinical cancers. Using in vitro model systems of toxicant-induced malignant transformation, we found hundreds of aberrant DNA methylation events that emerge during malignant transformation, some of which occur in an agglomerative fashion. In an arsenite-transformed prostate epithelial cell line, the protocadherin (PC DH), HOXC and HOXD gene family clusters are targeted for agglomerative DNA methylation. The agglomerative DNA methylation changes induced by arsenicals appear to be common and clinically relevant events, since they occur in other human cancer cell lines and models of malignant transformation, as well as clinical cancer specimens. Aberrant DNA methylation in general occurred more often within histone H3 lysine-27 trimethylation stem cell domains. We found a striking association between enrichment of histone H3 lysine-9 trimethylation stem cell domains and toxicant-induced agglomerative DNA methylation, suggesting these epigenetic modifications may become aberrantly linked during malignant transformation. In summary, we found an association between toxicant-induced malignant transformation and agglomerative DNA methylation, which lends further support to the hypothesis that epigenetic dysfunction plays an important role in toxicant-induced malignant transformation.

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KW - Cadmium

KW - DNA methylation

KW - Epigenetics

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KW - H3K9me3

KW - Long-range epigenetic silencing

KW - Malignant transformation

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Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation

Abstract

Keywords

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