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.

Item Type:	Refereed Article
Keywords:	Arsenic; DNA methylation; Histone acetylation; Keratinocytes; MiR-34a; Sirtuin 1
Research Division:	Biological Sciences
Research Group:	Genetics
Research Field:	Epigenetics (incl. genome methylation and epigenomics)
Objective Division:	Health
Objective Group:	Clinical health
Objective Field:	Clinical health not elsewhere classified
UTAS Author:	Herbert, KJ (Ms Katharine Herbert)
UTAS Author:	Holloway, A (Professor Adele Holloway)
UTAS Author:	Cook, AL (Associate Professor Tony Cook)
UTAS Author:	Chin, PS (Miss Paulynn Chin)
UTAS Author:	Snow, ET (Associate Professor Elizabeth Snow)
ID Code:	96565
Year Published:	2014
Web of Science® Times Cited:	21
Deposited By:	Menzies Institute for Medical Research
Deposited On:	2014-11-11
Last Modified:	2017-11-02
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