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Author Herbert, Katharine J. ♦ Holloway, Adele ♦ Cook, Anthony L. ♦ Chin, Suyin P. ♦ Snow, Elizabeth T.
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ACETYLATION ♦ ARSENIC ♦ CARCINOGENESIS ♦ CHROMATIN ♦ CONCENTRATION RATIO ♦ DNA ♦ DOSES ♦ GENE REGULATION ♦ GENES ♦ HUMAN POPULATIONS ♦ LYSINE ♦ MELANOMAS ♦ METHYL TRANSFERASES ♦ METHYLATION ♦ TOXINS
Abstract Arsenic is an environmental toxin which increases skin cancer risk for exposed populations worldwide; however the underlying biomolecular mechanism for arsenic-induced carcinogenesis is complex and poorly defined. Recent investigations show that histone deacetylase and DNA methyltransferase activity is impaired, and epigenetic patterns of gene regulation are consistently altered in cancers associated with arsenic exposure. Expression of the histone deacetylase SIRT1 is altered in solid tumours and haematological malignancies; however its role in arsenic-induced pathology is unknown. In this study we investigated the effect of arsenic on epigenetic regulation of SIRT1 and its targeting microRNA, miR-34a in primary human keratinocytes. Acetylation of histone H4 at lysine 16 (H4K16) increased in keratinocytes exposed to 0.5 μM arsenite [As(III)]; and this was associated with chromatin remodelling at the miR-34a promoter. Moreover, although SIRT1 protein initially increased in these As(III)-exposed cells, after 24 days expression was not significantly different from untreated controls. Extended exposure to low-dose As(III) (0.5 μM; > 5 weeks) compromised the pattern of CpG methylation at SIRT1 and miR-34a gene promoters, and this was associated with altered expression for both genes. We have found that arsenic alters epigenetic regulation of SIRT1 expression via structural reorganisation of chromatin at the miR-34a gene promoter in the initial 24 h of exposure; and over time, through shifts in miR-34a and SIRT1 gene methylation. Taken together, this investigation demonstrates that arsenic produces cumulative disruptions to epigenetic regulation of miR-34a expression, and this is associated with impaired coordination of SIRT1 functional activity. - Highlights: • Submicromolar arsenic concentrations disrupt SIRT1 activity and expression in human keratinocytes. • Arsenic-induced chromatin remodelling at the miR-34a gene promoter is associated with hyperacetylation of histone H4 (Lys 16). • Continual extended exposure to arsenic reorganises the pattern of SIRT1 and miR-34a promoter methylation.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2014-11-15
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 281
Issue Number 1


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