EPIGENETIC REMODELING DURING ARSENICAL-INDUCED MALIGNANT TRANSFORMATION

Persistent Link:
http://hdl.handle.net/10150/193558
Title:
EPIGENETIC REMODELING DURING ARSENICAL-INDUCED MALIGNANT TRANSFORMATION
Author:
Jensen, Taylor Jacob
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Humans are exposed to arsenicals through many routes with the most common being drinking water. Exposure to arsenic has been associated with an increased incidence of skin, lung, liver, prostate, and bladder cancer. Although the relationship between arsenic exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation and DNA methylation state of 13,000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation and DNA methylation occur during arsenical-induced malignant transformation, each of which is linked to the expression state of the associated gene. These epigenetic changes occurred non-randomly and targeted common promoters whether the selection was performed with arsenite [As(III)] or with the As(III) metabolite monomethylarsonous acid [MMA(III)]. The epigenetic alterations of these promoters and associated malignant phenotypes were stable after the removal of the transforming arsenical. One of the affected regions was the promoter of WNT5A. This gene is transcriptionally activated during arsenical induced malignant transformation and its promoter region exhibited alterations in each of the four histone modifications examined which were linked to its transcriptional activation. Experimental reduction of WNT5A transcript levels resulted in abrogated anchorage independent growth, suggesting a participative role for the epigenetic remodeling of this promoter region in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by stably altering the DNA methylation and histone modifications associated with targeted genes, uncovering a likely set of participative genes and representing a mechanism to potentially explain the latency associated with arsenic-induced malignancy.
Type:
text; Electronic Dissertation
Keywords:
Arsenic; Carcinogenesis; DNA Methylation; Epigenetic; Histone Acetylation; MMA(III)
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Futscher, Bernard W
Committee Chair:
Futscher, Bernard W

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleEPIGENETIC REMODELING DURING ARSENICAL-INDUCED MALIGNANT TRANSFORMATIONen_US
dc.creatorJensen, Taylor Jacoben_US
dc.contributor.authorJensen, Taylor Jacoben_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractHumans are exposed to arsenicals through many routes with the most common being drinking water. Exposure to arsenic has been associated with an increased incidence of skin, lung, liver, prostate, and bladder cancer. Although the relationship between arsenic exposure and carcinogenesis is well documented, the mechanisms by which arsenic participates in tumorigenesis are not fully elucidated. We evaluated the potential epigenetic component of arsenical action by assessing the histone acetylation and DNA methylation state of 13,000 human gene promoters in a cell line model of arsenical-mediated malignant transformation. We show changes in histone H3 acetylation and DNA methylation occur during arsenical-induced malignant transformation, each of which is linked to the expression state of the associated gene. These epigenetic changes occurred non-randomly and targeted common promoters whether the selection was performed with arsenite [As(III)] or with the As(III) metabolite monomethylarsonous acid [MMA(III)]. The epigenetic alterations of these promoters and associated malignant phenotypes were stable after the removal of the transforming arsenical. One of the affected regions was the promoter of WNT5A. This gene is transcriptionally activated during arsenical induced malignant transformation and its promoter region exhibited alterations in each of the four histone modifications examined which were linked to its transcriptional activation. Experimental reduction of WNT5A transcript levels resulted in abrogated anchorage independent growth, suggesting a participative role for the epigenetic remodeling of this promoter region in arsenical-induced malignant transformation. Taken together, these data suggest that arsenicals may participate in tumorigenesis by stably altering the DNA methylation and histone modifications associated with targeted genes, uncovering a likely set of participative genes and representing a mechanism to potentially explain the latency associated with arsenic-induced malignancy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectArsenicen_US
dc.subjectCarcinogenesisen_US
dc.subjectDNA Methylationen_US
dc.subjectEpigeneticen_US
dc.subjectHistone Acetylationen_US
dc.subjectMMA(III)en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorFutscher, Bernard Wen_US
dc.contributor.chairFutscher, Bernard Wen_US
dc.contributor.committeememberGandolfi, A. Jayen_US
dc.contributor.committeememberCherrington, Nathanen_US
dc.contributor.committeememberCamenisch, Todden_US
dc.identifier.proquest10188en_US
dc.identifier.oclc659750772en_US
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