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Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure
- Source :
- Toxicology and applied pharmacology. 241(3)
- Publication Year :
- 2009
-
Abstract
- Arsenic, a human carcinogen that is associated with an increased risk of bladder cancer, is commonly found in drinking water. An important mechanism by which arsenic is thought to be carcinogenic is through the induction of epigenetic changes that lead to aberrant gene expression. Previously, we reported that the SAS2 gene is required for optimal growth of yeast in the presence of arsenite (As(III)). Yeast Sas2p is orthologous to human MYST1, a histone 4 lysine 16 (H4K16) acetyltransferase. Here, we show that H4K16 acetylation is necessary for the resistance of yeast to As(III) through the modulation of chromatin state. We further explored the role of MYST1 and H4K16 acetylation in arsenic toxicity and carcinogenesis in human bladder epithelial cells. The expression of MYST1 was knocked down in UROtsa cells, a model of bladder epithelium that has been used to study arsenic-induced carcinogenesis. Silencing of MYST1 reduced acetylation of H4K16 and induced sensitivity to As(III) and to its more toxic metabolite monomethylarsonous acid (MMA(III)) at doses relevant to high environmental human exposures. In addition, both As(III) and MMA(III) treatments decreased global H4K16 acetylation levels in a dose- and time-dependent manner. This indicates that acetylated H4K16 is required for resistance to arsenic and that a reduction in its levels as a consequence of arsenic exposure may contribute to toxicity in UROtsa cells. Based on these findings, we propose a novel role for the MYST1 gene in human sensitivity to arsenic.
- Subjects :
- Blotting, Western
Urinary Bladder
chemistry.chemical_element
Tetrazolium Salts
Saccharomyces cerevisiae
Biology
Toxicology
medicine.disease_cause
Arsenicals
Mass Spectrometry
Article
chemistry.chemical_compound
medicine
Humans
Epigenetics
Gene Silencing
Coloring Agents
Arsenic
Carcinogen
Arsenite
Histone Acetyltransferases
Pharmacology
Arsenic toxicity
Dose-Response Relationship, Drug
Reverse Transcriptase Polymerase Chain Reaction
Acetylation
Epithelial Cells
Chromatin
Thiazoles
Retroviridae
chemistry
Biochemistry
Toxicity
Cancer research
Carcinogenesis
Subjects
Details
- ISSN :
- 10960333
- Volume :
- 241
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Toxicology and applied pharmacology
- Accession number :
- edsair.doi.dedup.....0130774f8230d24a39d0becbd515c78b