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E2F1-Mediated FOS Induction in Arsenic Trioxide-Induced Cellular Transformation: Effects of Global H3K9 Hypoacetylation and Promoter-Specific Hyperacetylation in Vitro

Title: E2F1-Mediated FOS Induction in Arsenic Trioxide-Induced Cellular Transformation: Effects of Global H3K9 Hypoacetylation and Promoter-Specific Hyperacetylation in Vitro
Authors: Rahman, S
Housein, Z
Dabrowska, A
Dolores Mayan, M
Boobis, AR
Hajji, N
Item Type: Journal Article
Abstract: Background: Aberrant histone acetylation has been observed in carcinogenesis and cellular transformation associated with arsenic exposure; however, the molecular mechanisms and cellular outcomes of such changes are poorly understood. Objective: We investigated the impact of tolerated and toxic arsenic trioxide (As2O3) exposure in human embryonic kidney (HEK293T) and urothelial (UROtsa) cells to characterize the alterations in histone acetylation and gene expression as well as the implications for cellular transformation. Methods: Tolerated and toxic exposures of As2O3 were identified by measurement of cell death, mitochondrial function, cellular proliferation, and anchorage-independent growth. Histone extraction, the MNase sensitivity assay, and immunoblotting were used to assess global histone acetylation levels, and gene promoter-specific interactions were measured by chromatin immunoprecipitation followed by reverse-transcriptase polymerase chain reaction. Results: Tolerated and toxic dosages, respectively, were defined as 0.5 μM and 2.5 μM As2O3 in HEK293T cells and 1 μM and 5 μM As2O3 in UROtsa cells. Global hypoacetylation of H3K9 at 72 hr was observed in UROtsa cells following tolerated and toxic exposure. In both cell lines, tolerated exposure alone led to H3K9 hyperacetylation and E2F1 binding at the FOS promoter, which remained elevated after 72 hr, contrary to global H3K9 hypoacetylation. Thus, promoter-specific H3K9 acetylation is a better predictor of cellular transformation than are global histone acetylation patterns. Tolerated exposure resulted in an increased expression of the proto-oncogenes FOS and JUN in both cell lines at 72 hr. Conclusion: Global H3K9 hypoacetylation and promoter-specific hyperacetylation facilitate E2F1-mediated FOS induction in As2O3-induced cellular transformation.
Issue Date: 9-Jan-2015
Date of Acceptance: 6-Jan-2015
URI: http://hdl.handle.net/10044/1/48690
DOI: https://dx.doi.org/10.1289/ehp.1408302
ISSN: 0091-6765
Publisher: National Institute of Environmental Health Sciences
Start Page: 484
End Page: 492
Journal / Book Title: Environmental Health Perspectives
Volume: 123
Issue: 5
Copyright Statement: Public Domain. Rahman S, Housein Z, Dabrowska A, Mayán MD, Boobis AR, Hajji N. 2015. E2F1-mediated FOS induction in arsenic trioxide–induced cellular transformation: effects of global H3K9 hypoacetylation and promoter-specific hyperacetylation in vitro. Environmental Health Perspectives 123:484–492; http://dx.doi.org/10.1289/ehp.1408302. Reproduced with permission from Environmental Health Perspectives
Keywords: Science & Technology
Life Sciences & Biomedicine
Environmental Sciences
Public, Environmental & Occupational Health
Toxicology
Environmental Sciences & Ecology
ACUTE PROMYELOCYTIC LEUKEMIA
NEOPLASTIC TRANSFORMATION
HISTONE MODIFICATIONS
OXIDATIVE STRESS
WELL WATER
EXPOSURE
CELLS
ACETYLATION
METHYLATION
CHROMATIN
Acetylation
Arsenicals
Cell Line
Chromatin Immunoprecipitation
Chromatography, Reverse-Phase
E2F1 Transcription Factor
HEK293 Cells
Histones
Humans
Immunoblotting
Oxides
Promoter Regions, Genetic
11 Medical And Health Sciences
05 Environmental Sciences
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)