Acetylated H4K16 by MYST1 protects UROtsa cells from arsenic toxicity and is decreased following chronic arsenic exposure

Journal Article · Tue Dec 15 04:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.08.027· OSTI ID:21344812

Ren, Xuefeng ^[1]; Chu, Feixia ^[2]; Aleshin, Maria ^[1]; Wintz, Henri ^[3]; Burlingame, Alma ^[2]

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1. Department of Environmental Health Sciences, School of Public Health, University of California Berkeley, Berkeley, CA 94720 (United States)
2. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158 (United States)
3. Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720 (United States)

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{sup 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{sup 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{sup III} and to its more toxic metabolite monomethylarsonous acid (MMA{sup III}) at doses relevant to high environmental human exposures. In addition, both As{sup III} and MMA{sup 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.

• OSTI ID: 21344812
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 241; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACETYLATION
ACYLATION
AMINO ACIDS
ANIMAL TISSUES
ANIMALS
ARSENIC
BLADDER
BODY
CARBOXYLIC ACIDS
CARCINOGENESIS
CARCINOGENS
CHEMICAL REACTIONS
CHROMATIN
DISEASES
DOSES
DRINKING WATER
ELEMENTS
EPITHELIUM
EUMYCOTA
FUNGI
GENES
HYDROGEN COMPOUNDS
LYSINE
MALES
MAMMALS
MAN
MEN
MICROORGANISMS
NEOPLASMS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PATHOGENESIS
PLANTS
PRIMATES
SEMIMETALS
SENSITIVITY
TOXICITY
URINARY TRACT
VERTEBRATES
WATER
YEASTS