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

Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 10/2009; 241(3):294-302. DOI: 10.1016/j.taap.2009.08.027
Source: PubMed


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.

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    • "An increasing body of evidence suggests that posttranslational histone modifications, particularly histone acetylation, can influence overall chromatin structure and gene transcription, with clear functional consequences in cellular processes such as prolifera tion and apoptosis (Füllgrabe et al. 2010). Suitably, alterations of histone modification as a result of arsenic exposure have been identified, particularly changes in phosphorylation, methylation, and acetylation; however, relating such modifications to a mechanistic outcome has been limited (Jo et al. 2009; Li et al. 2002; Zhou et al. 2008). "
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    ABSTRACT: 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. We investigated the impact of tolerated and toxic As2O3 exposure in human embryonic kidney (HEK293T) and urothelial (UROtsa) cells to characterise the alterations in histone acetylation, gene expression and the implications for cellular transformation. Tolerated and toxic exposures of As2O3 were identified by measurement of cell death, mitochondrial function, cellular proliferation and anchorage-independent growth. Histone extraction, 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. Tolerated and toxic dosages were defined as 0.5 µM and 2.5 µM As2O3 in HEK293T cells and 1 µM and 5 µM As2O3 in UROtsa cells respectively. Global hypo-acetylation of H3K9 at 72 hours was observed in UROtsa cells following tolerated and toxic exposure. In both cell lines, tolerated exposure alone led to H3K9 hyper-acetylation and E2F1 binding at the FOS promoter, which remained elevated after 72 hours contrary to global H3K9 hypo-acetylation. Thus, promoter specific H3K9 acetylation is a better predictor of cellular transformation than global histone acetylation patterns. Tolerated exposure resulted in an increased expression of proto-oncogenes FOS and JUN in both cell lines at 72 hours. Global H3K9 hypo-acetylation and promoter-specific hyper-acetylation facilitate E2F1-mediated FOS induction in As2O3-induced cellular transformation.
    Environmental Health Perspectives 01/2015; 123(5). DOI:10.1289/ehp.1408302 · 7.98 Impact Factor
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    • "For example, Ishizaki et al. (2010) utilized a yeast chemical-genetic screen to reveal that intracellular trafficking defects conferred sensitivity to copper limitation, and further reported that knockdown of zebrafish homologs to these yeast genes sensitized fish to copper-dependent hypopigmentation, a hallmark of copper deficiency in humans. Following identification of the Sas2p histone acetyltransferase as a modulator of arsenite tolerance in yeast, knockdown of its homolog MYST1 in human bladder epithelial cells was found to similarly induce arsenite sensitivity (Jo et al., 2009a,b). Another group demonstrated that the investigational cancer drug elesclomol affected electron transport mutants in yeast and extended their analysis by determining that elesclomol interacted with the electron transport chain in human cells (Blackman et al., 2012). "
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    ABSTRACT: The increased presence of chemical contaminants in the environment is an undeniable concern to human health and ecosystems. Historically, by relying heavily upon costly and laborious animal-based toxicity assays, the field of toxicology has often neglected examinations of the cellular and molecular mechanisms of toxicity for the majority of compounds-information that, if available, would strengthen risk assessment analyses. Functional toxicology, where cells or organisms with gene deletions or depleted proteins are used to assess genetic requirements for chemical tolerance, can advance the field of toxicity testing by contributing data regarding chemical mechanisms of toxicity. Functional toxicology can be accomplished using available genetic tools in yeasts, other fungi and bacteria, and eukaryotes of increased complexity, including zebrafish, fruit flies, rodents, and human cell lines. Underscored is the value of using less complex systems such as yeasts to direct further studies in more complex systems such as human cell lines. Functional techniques can yield (1) novel insights into chemical toxicity; (2) pathways and mechanisms deserving of further study; and (3) candidate human toxicant susceptibility or resistance genes.
    Frontiers in Genetics 05/2014; 5:110. DOI:10.3389/fgene.2014.00110
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    • "Lysine acetylation, the best-known type of lysine acylation PTM, regulates various crucial roles in biological systems (9). In current review, we consider toxicity to originate from the abnormal regulation of lysine acetylation, such as, the dysregulation of modulating enzymes like acetyltransferase/deacetylase, the blocking of protein acetylation at specific lysine residues and the subsequent modulation of protein functions, and the dysregulation of histone acetylation as an epigenetic marker (24,26,30). However, new types of lysine acylations, such as, propionylation, butyrylation, malonylation, succinylation, and crotonylation continue to be detected, and their biological roles have yet to be determined. "
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    ABSTRACT: Toxicoproteomics integrates the proteomic knowledge into toxicology by enabling protein quantification in biofluids and tissues, thus taking toxicological research to the next level. Post-translational modification (PTM) alters the three-dimensional (3D) structure of proteins by covalently binding small molecules to them and therefore represents a major protein function diversification mechanism. Because of the crucial roles PTM plays in biological systems, the identification of novel PTMs and study of the role of PTMs are gaining much attention in proteomics research. Of the 300 known PTMs, protein acylation, including lysine formylation, acetylation, propionylation, butyrylation, malonylation, succinylation, and crotonylation, regulates the crucial functions of many eukaryotic proteins involved in cellular metabolism, cell cycle, aging, growth, angiogenesis, and cancer. Here, I reviewed recent studies regarding novel types of lysine acylation, their biological functions, and their applicationsin toxicoproteomics research.
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