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1.  Chromatin Memory in the Development of Human Cancers 
Gene technology  2014;3(2):114-.
Cancer is a complex disease with acquired genomic and epigenomic alterations that affect cell proliferation, viability and invasiveness. Almost all the epigenetic mechanisms including cytosine methylation and hydroxymethylation, chromatin remodeling and non-coding RNAs have been found associate with carcinogenesis and cancer specific expression profile. Altered histone modification as an epigenetic hallmark is frequently found in tumors. Understanding the epigenetic alterations induced by carcinogens or infectious agents may help us understand early epigenetic changes prior to the development of cancer. In this review, we focus on chromatin remodeling and the associated histone modifiers in the development of cancer; the application of these modifiers as a cancer therapy target in different clinical trial phases is also discussed.
PMCID: PMC4297643  PMID: 25606572
Cancer epigenetics; Histone modifications; Methylation; Acetylation; Chromatin
2.  Particulate matter from Saudi Arabia induces genes involved in inflammation, metabolic syndrome and atherosclerosis 
Airborne particulate matter (PM) exposure is a major environmental health concern and is linked to metabolic disorders, such as cardiovascular diseases (CVD) and diabetes, which are on the rise in the Kingdom of Saudi Arabia. This study investigated changes in mouse lung gene expression produced by administration of PM10 collected from Jeddah, Saudi Arabia. FVB/N mice were exposed to 100 µg PM10 or water by aspiration and euthanized 24 hr later. The bronchoalveolar lavage fluid (BALF) was collected and analyzed for neutrophil concentration and TNF-α and IL-6 levels. RNA was extracted from the lungs and whole transcript was analyzed using Affymetrix Mouse Gene 1.0 ST Array. Mice exposed to PM10 displayed an increase in neutrophil concentration and elevated TNF-α and IL-6 levels. Gene expression analysis revealed that mice exposed to PM10 displayed 202 genes that were significantly up-regulated and 40 genes that were significantly down-regulated. PM10 induced genes involved in inflammation, cholesterol and lipid metabolism, as well as atherosclerosis. This is the first study to demonstrate that Saudi Arabia PM10 increases in vivo expression of genes located in pathways associated with diseases involving metabolic syndrome and atherosclerosis.
doi:10.1080/15287394.2014.892446
PMCID: PMC4233653  PMID: 24839929
gene expression; metabolic diseases; lungs; cholesterol; particulate matter; mouse
3.  Epigenomics: Pioneering a New Frontier in Cancer Research 
doi:10.4172/2153-0645.1000e109
PMCID: PMC4118684  PMID: 25089224
4.  Structural Investigations of the Nickel-Induced Inhibition of Truncated Constructs of the JMJD2 Family of Histone Demethylases Using X-ray Absorption Spectroscopy 
Biochemistry  2013;52(24):4168-4183.
Occupational and/or environmental exposure to nickel has been implicated in various types of cancer, and in vitro exposure to nickel compounds results in accumulation of Ni(II) ions in cells. One of the major targets of Ni(II) ions inside the cell is Fe(II)- and αKG-dependent dioxygenases. Using JMJD2A and JMJD2C as examples, we show that JMJD2 family of histone demethylases, which are products of putative oncogenes as well as Fe(II)- and αKG-dependent dioxygenases, are highly sensitive to inhibition by Ni(II) ions. In this work, X-ray absorption spectroscopy (XAS) has been used to investigate the Fe(II) active site of truncated JMJD2A and JMJD2C (1 – 350 aa) in the presence and absence of αKG and/or substrate to obtain mechanistic details of the early steps in catalysis that precede O2 binding in histone demethylation by the JMJD2 family of histone demethylases. Zinc K-edge XAS has been performed on the resting JMJD2A (with iron in the active site) to confirm the presence of the expected structural zinc site. XAS of the Ni(II)-substituted enzymes has also been performed to investigate the inhibition of these enzymes by Ni(II) ions. Our XAS results indicate that the five-coordinate Fe(II) center in the resting enzyme is retained in the binary and ternary complexes. In contrast, the Ni(II) center is six-coordinate in the resting enzyme, binary and ternary complexes. XAS results indicate that both Fe(II) and Ni(II) bind αKG in the binary and ternary complexes. The electron density build-up that is observed at the Fe(II) center in the presence of αKG and substrate is not observed at the Ni(II) center. Thus, both electronic and steric factors are responsible for Ni-induced inhibition of the JMJD2 family of histone demethylases. Ni-induced inhibition of these enzymes may explain the alteration of the epigenetic mechanism of gene expression that is responsible for Ni-induced carcinogenesis.
doi:10.1021/bi400274v
PMCID: PMC3746964  PMID: 23692052
5.  Plasma Anti-Glycan Antibody Profiles Associated with Nickel level in Urine 
Nickel (Ni) compounds are widely used in industrial and commercial products including household and cooking utensils, jewelry, dental appliances and implants. Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers, is the most common cause of contact dermatitis and has an extensive effect on the immune system. The purpose of this study was two-fold: (i) to evaluate immune response to the occupational exposure to nickel measured by the presence of anti-glycan antibodies (AGA) using a new biomarker-discovery platform based on printed glycan arrays (PGA), and (ii) to evaluate and compile a sequence of bioinformatics and statistical methods which are specifically relevant to PGA-derived information and to identification of putative “Ni toxicity signature”. The PGAs are similar to DNA microarrays, but contain deposits of various carbohydrates (glycans) instead of spotted DNAs.
The study uses data derived from a set of 89 plasma specimens and their corresponding demographic information. The study population includes three subgroups: subjects directly exposed to Nickel that work in a refinery, subjects environmentally exposed to Nickel that live in a city where the refinery is located and subjects that live in a remote location. The paper describes the following sequence of nine data processing and analysis steps: (1) Analysis of inter-array reproducibility based on benchmark sera; (2) Analysis of intra-array reproducibility; (3) Screening of data - rejecting glycans which result in low intra-class correlation coefficient (ICC), high coefficient of variation and low fluorescent intensity; (4) Analysis of inter-slide bias and choice of data normalization technique; (5) Determination of discriminatory subsamples based on multiple bootstrap tests; (6) Determination of the optimal signature size (cardinality of selected feature set) based on multiple cross-validation tests; (7) Identification of the top discriminatory glycans and their individual performance based on nonparametric univariate feature selection; (8) Determination of multivariate performance of combined glycans; (9) Establishing the statistical significance of multivariate performance of combined glycan signature.
The above analysis steps have delivered the following results: inter-array reproducibility ρ=0.920 ± 0.030; intra-array reproducibility ρ=0.929 ± 0.025; 249 out of 380 glycans passed the screening at ICC>80%, glycans in selected signature have ICC ≥ 88.7%; optimal signature size (after quantile normalization)=3; individual significance for the signature glycans p=0.00015 to 0.00164, individual AUC values 0.870 to 0.815; observed combined performance for three glycans AUC=0.966, p=0.005, CI=[0.757, 0947]; specifity=94.4%, sensitivity=88.9%; predictive (cross-validated) AUC value 0.836.
doi:10.4172/jpb.1000295
PMCID: PMC3984841  PMID: 24737927
Printed glycan arrays; Immune response to occupational exposure to Nickel; Plasma anti-glycan antibodies; Quality analysis of printed glycan arrays; Immunoprofiling; Discriminatory signatures; Immunoruler
6.  Sodium metavanadate exhibits carcinogenic tendencies in vitro in immortalized human bronchial epithelial cells† 
Pentavalent vanadium compounds induce intracellular changes in vitro that are consistent with those of other carcinogenic substances. While there is no clear evidence that vanadium compounds cause cancer in humans, vanadium pentoxide causes lung cancer in rodents after long-term inhalation exposures and in turn IARC has categorized it as a group 2B possible human carcinogen. The goal of this study was to investigate the carcinogenicity of NaVO3 in the human immortalized bronchial epithelial cell line, Beas-2B. Cells were treated with 10 μM NaVO3 for 5 weeks, with or without recovery time, followed by gene expression microarray analysis. In a separate experiment, cells were exposed to 1–10 μM NaVO3 for 4 weeks and then grown in soft agar to test for anchorage-independent growth. A dose-dependent increase in the number of colonies was observed. In scratch tests, NaVO3-transformed clones could repair a wound faster than controls. In a gene expression microarray analysis of soft agar clones there were 2010 differentially expressed genes (DEG) (adjusted p-value ≤ 0.05) in NaVO3-transformed clones relative to control clones. DEG from this experiment were compared with the DEG of 5 week NaVO3 exposure with or without recovery, all with adjusted p-values < 0.05, and 469 genes were altered in the same direction for transformed clones, 5 week NaVO3-treated cells, and the recovered cells. The data from this study imply that chronic exposure to NaVO3 causes changes that are consistent with cellular transformation including anchorage-independent growth, enhanced migration ability, and gene expression changes that were likely epigenetically inherited.
doi:10.1039/c3mt00149k
PMCID: PMC3982314  PMID: 23963610
7.  Roles of MAPK Pathway Activation During Cytokine Induction in BEAS-2B Cells Exposed to Fine World Trade Center (WTC) Dust 
Journal of immunotoxicology  2010;7(4):298-307.
The World Trade Center (WTC) collapse on September 11, 2001 released copious amounts of particulate matter into the atmosphere of New York City. Follow-up studies on persons exposed to the dusts have revealed a severely increased rate for asthma and other respiratory illnesses. There have only been a few studies that have sought to discern the possible mechanisms underlying these untoward pathologies. In one study, an increased cytokine release was detected in cells exposed to WTC fine dusts (PM2.5 fraction or WTC2.5). However, the mechanism(s) for these increases has yet to be fully defined. Because activation of the MAPK signaling pathways is known to cause cytokine induction, the current study was undertaken to analyze the possible involvement of these pathways in any increased cytokine formation by lung epithelial cells (as BEAS-2B cells) exposed to WTC2.5. Our results showed that exposure to WTC2.5 for 5 hr increased IL-6 mRNA expression in BEAS-2B cells, as well as its protein levels in the culture media, in a dose-dependent manner. Besides IL-6, Cytokine Multiplex analyses revealed that formation of IL-8 and -10 was also elevated by the exposure. Both ERK and p38, but not JNK, signaling pathways were found to be activated in cells exposed to WTC2.5. Inactivation of ERK signaling pathways by PD98059 effectively blocked IL-6, -8, and -10 induction by WTC2.5; the p38 kinase inhibitor SB203580 significantly decreased induction of IL-8 and -10. Together, our data demonstrated activation of MAPK signaling pathway(s) likely played an important role in the WTC2.5-induced formation of several inflammatory (and, subsequently, anti-inflammatory) cytokines. The results are important in that they help to define one mechanism via which the WTC dusts may have acted to cause the documented increases in asthma and other inflammation-associated respiratory dysfunctions in the individuals exposed to the dusts released from the WTC collapse.
doi:10.3109/1547691X.2010.509289
PMCID: PMC3966203  PMID: 20731619
PM2.5; interleukin (IL)-6; IL-8; IL-10; ERK; p38
8.  Source Apportionment and Elemental Composition of PM2.5 and PM10 in Jeddah City, Saudi Arabia 
Atmospheric pollution research  2012;3(3):331-340.
This paper presents the first comprehensive investigation of PM2.5 and PM10 composition and sources in Saudi Arabia. We conducted a multi-week multiple sites sampling campaign in Jeddah between June and September, 2011, and analyzed samples by XRF. The overall mean mass concentration was 28.4 ± 25.4 μg/m3 for PM2.5 and 87.3 ± 47.3 μg/m3 for PM10, with significant temporal and spatial variability. The average ratio of PM2.5/PM10 was 0.33. Chemical composition data were modeled using factor analysis with varimax orthogonal rotation to determine five and four particle source categories contributing significant amount of for PM2.5 and PM10 mass, respectively. In both PM2.5 and PM10 sources were (1) heavy oil combustion characterized by high Ni and V; (2) resuspended soil characterized by high concentrations of Ca, Fe, Al, and Si; and (3) marine aerosol. The two other sources in PM2.5 were (4) Cu/Zn source; (5) traffic source identified by presence of Pb, Br, and Se; while in PM10 it was a mixed industrial source. To estimate the mass contributions of each individual source category, the CAPs mass concentration was regressed against the factor scores. Cumulatively, resuspended soil and oil combustion contributed 77 and 82% mass of PM2.5 and PM10, respectively.
PMCID: PMC3951168  PMID: 24634602
9.  Serum taurine and risk of coronary heart disease: a prospective, nested case-control study 
European journal of nutrition  2012;52(1):169-178.
Purpose
Taurine (2-aminoethanesulfonic acid), a molecule obtained from diet, is involved in bile acid conjugation, blood pressure regulation, anti-oxidation and anti-inflammation. We performed the first prospective study of taurine and CHD risk.
Methods
We conducted a case-control study nested in the New York University Women’s Health Study to evaluate the association between circulating taurine levels and risk of coronary heart disease (CHD). Taurine was measured in two yearly pre-diagnostic serum samples of 223 CHD cases and 223 matched controls and averaged for a more reliable measurement of long-term taurine levels.
Results
Mean serum taurine was positively related to age and dietary intake of poultry, niacin, vitamin B1, fiber, and iron, and negatively related to dietary intake of saturated fat (all p values ≤ 0.05). There was no statistically significant association between the risk of CHD and serum taurine levels. The adjusted ORs for CHD in increasing taurine tertiles were 1.0 (reference), 0.85 (95% CI, 0.51–1.40), and 0.66 (0.39–1.13; p for trend = 0.14). There was a significant inverse association between serum taurine and CHD risk among women with high total serum cholesterol (>250 mg/dl) (adjusted OR = 0.39 (0.19–0.83) for the third vs. first tertile; p for trend = 0.02) but not among those with low total serum cholesterol (p for interaction = 0.01). The data suggest a possible inverse association of serum taurine with diabetes and hypertension risk.
Conclusions
The findings suggest that high levels of taurine may be protective against CHD among individuals with high serum cholesterol levels.
doi:10.1007/s00394-011-0300-6
PMCID: PMC3920833  PMID: 22322924
Taurine; serum; coronary heart disease; NYUWHS; epidemiology
10.  Gene expression profiles in peripheral blood mononuclear cells of Chinese nickel refinery workers with high exposures to nickel and control subjects 
Background
Occupational exposure to nickel (Ni) is associated with an increased risk of lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, alter the cell’s epigenetic homeostasis, and activate signaling pathways. However, changes in gene expression associated with Ni exposure have only been investigated in vitro. This study was conducted in a Chinese population to determine whether occupational exposure to Ni was associated with differential gene expression profiles in the peripheral blood mononuclear cells (PBMCs) of Ni-refinery workers when compared to referents.
Methods
Eight Ni-refinery workers and ten referents were selected. PBMC RNA was extracted and gene expression profiling was performed using Affymetrix exon arrays. Differentially expressed genes between both groups were identified in a global analysis.
Results
There were a total of 2756 differentially expressed genes (DEG) in the Ni-refinery workers relative to the control subjects (FDR adjusted p<0.05) with 770 up-regulated genes and 1986 down-regulated genes. DNA repair and epigenetic genes were significantly overrepresented (p< 0.0002) among the DEG. Of 31 DNA repair genes, 29 were repressed in the high exposure group and two were overexpressed. Of the 16 epigenetic genes 12 were repressed in the high exposure group and 4 were overexpressed.
Conclusions
The results of this study indicate that occupational exposure to Ni is associated with alterations in gene expression profiles in PBMCs of subjects.
Impact
Gene expression may be useful in identifying patterns of deregulation that precede clinical identification of Ni-induced cancers.
doi:10.1158/1055-9965.EPI-12-1011
PMCID: PMC3565097  PMID: 23195993
nickel; nickel refinery workers; gene expression; metals; carcinogenesis
11.  Gene expression profiling and pathway analysis of human bronchial epithelial cells exposed to airborne particulate matter collected from Saudi Arabia 
Toxicology and applied pharmacology  2012;265(2):10.1016/j.taap.2012.10.008.
Epidemiological studies have established a positive correlation between human mortality and increased concentration of airborne particulate matters (PM). However, the mechanisms underlying PM related human diseases, as well as the molecules and pathways mediating the cellular response to PM, are not fully understood. This study aims to investigate the global gene expression changes in human cells exposed to PM10 and to identify genes and pathways that may contribute to PM related adverse health effects. Human bronchial epithelial cells were exposed to PM10 collected from Saudi Arabia for 1 or 4 days, and whole transcript expression was profiled using the GeneChip human gene 1.0 ST array. A total of 140 and 230 genes were identified that significantly changed more than 1.5 fold after PM10 exposure for 1 or 4 days, respectively. Ingenuity Pathway Analysis revealed that different exposure durations triggered distinct pathways. Genes involved in NRF2-mediated response to oxidative stress were up-regulated after 1 day exposure. In contrast, cells exposed for 4 days exhibited significant changes in genes related to cholesterol and lipid synthesis pathways. These observed changes in cellular oxidative stress and lipid synthesis might contribute to PM related respiratory and cardiovascular disease.
doi:10.1016/j.taap.2012.10.008
PMCID: PMC3883356  PMID: 23085030
particulate matter; gene expression; human bronchial epithelial cells; Microarray; Ingenuity pathway analysis
12.  Basic Mechanics of DNA Methylation and the Unique Landscape of the DNA Methylome in Metal-Induced Carcinogenesis 
Critical reviews in toxicology  2013;43(6):10.3109/10408444.2013.794769.
DNA methylation plays an intricate role in the regulation of gene expression and events that compromise the integrity of the methylome may potentially contribute to disease development. DNA methylation is a reversible and regulatory modification that elicits a cascade of events leading to chromatin condensation and gene silencing. In general, normal cells are characterized by gene-specific hypomethylation and global hypermethylation, while cancer cells portray a reverse profile to this norm. The unique methylome displayed in cancer cells is induced after exposure to carcinogenic metals such as nickel, arsenic, cadmium, and chromium (VI). These metals alter the DNA methylation profile by provoking both hyper- and hypomethylation events. The metal-stimulated deviations to the methylome are possible mechanisms for metal-induced carcinogenesis and may provide potential biomarkers for cancer detection. Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance.
doi:10.3109/10408444.2013.794769
PMCID: PMC3871623  PMID: 23844698
DNA methylation; metals; hypomethylation; hypermethylation; promoter methylation; nickel; arsenic; chromium; cadmium; cancer; methylome; metal carcinogenesis; 5mC; DNMT; tet proteins
13.  Association Between Arsenic Exposure and Global Post-translational Histone Modifications Among Adults in Bangladesh 
Background
Exposure to arsenic (As) is associated with an increased risk of several cancers, as well as, cardiovascular disease, and childhood neuro-developmental deficits. Arsenic compounds are weakly mutagenic, alter gene expression and post-translational histone modifications (PTHMs) in vitro.
Methods
Water and urinary As concentrations, as well as, global levels of histone 3 lysine 9 di-methylation and acetylation (H3K9me2 and H3K9ac), histone 3 lysine 27 trimethylation and acetylation (H3K27me3 and H3K27ac), histone 3 lysine 18 acetylation (H3K18ac) and histone 3 lysine 4 trimethylation (H3K4me3) were measured in peripheral blood mononuclear cells (PBMCs) from a subset of participants (N=40) of a folate clinical trial in Bangladesh (FACT study).
Results
Total urinary As (uAs) was positively correlated with H3K9me2 (r=0.36, p=0.02) and inversely with H3K9ac (r= -0.47, p=0.002). The associations between As and other PTHMs differed in a gender-dependent manner. Water As (wAs) was positively correlated with H3K4me3 (r=0.45, p=0.05) and H3K27me3 (r=0.50, p=0.03) among females and negatively correlated among males (H3K4me3: r= -0.44, p=0.05; H3K27me3: r= -0.34, p=0.14). Conversely, wAs was inversely associated with H3K27ac among females (r= -0.44, p=0.05) and positively associated among males (r=0.29, p=0.21). A similar pattern was observed for H3K18ac (females: r= -0.22, p=0.36; males: r=0.27, p=0.24).
Conclusion
Exposure to As is associated with alterations of global PTHMs; gender-specific patterns of association were observed between As exposure and several histone marks.
Impact
These findings contribute to the growing body of evidence linking As exposure to epigenetic dysregulation, which may play a role in the pathogenesis of As toxicity.
doi:10.1158/1055-9965.EPI-12-0833
PMCID: PMC3518638  PMID: 23064002
Arsenic; epigenetics; histone modifications; Bangladesh; gender difference
14.  Nickel and Epigenetic Gene Silencing 
Genes  2013;4(4):583-595.
Insoluble nickel compounds are well-established human carcinogens. Occupational exposure to these compounds leads to increased incidence of lung and nasal cancer in nickel refinery workers. Apart from its weak mutagenic activity and hypoxia mimicking effect there is mounting experimental evidence indicating that epigenetic alteration plays an important role in nickel-induced carcinogenesis. Multiple epigenetic mechanisms have been identified to mediate nickel-induced gene silencing. Nickel ion is able to induce heterochromatinization by binding to DNA-histone complexes and initiating chromatin condensation. The enzymes required for establishing or removing epigenetic marks can be targeted by nickel, leading to altered DNA methylation and histone modification landscapes. The current review will focus on the epigenetic changes that contribute to nickel-induced gene silencing.
doi:10.3390/genes4040583
PMCID: PMC3927569  PMID: 24705264
epigenetics; gene silencing; heterochromatin; DNA methylation; histone modification; miRNA
15.  The control of histone methylation and gene expression by oxidative stress, hypoxia and metals 
Free radical biology & medicine  2012;53(5):1041-1047.
The harmful consequences of carcinogenic metals, such as nickel, arsenic and chromium, are thought to be in part due to their ability to induce oxidative stress. The ubiquity of oxidative stress in biological systems has made it a fairly obvious culprit in causing cellular damage and/or development of disease. However, the full extent of oxidative stress-induced damage is not limited to its direct effects on cellular components, such as lipids, proteins and DNA, but may extend to its ability to alter gene expression. Gene expression regulation is an important component of cellular and/or tissue homeostasis, and its alteration can have detrimental consequences. Therefore, a growing amount of interest is being paid to understanding how oxidative stress can influence gene expression. Oxidative stress-induced epigenetic dysregulation in the form of post-translational histone modifications, in particular, is a popular topic of research. This review will therefore primarily focus on discussing the role of oxidative stress and hypoxia on histone methylation and/or gene expression alterations. The sources of oxidative stress discussed here are carcinogenic metals, such as, nickel, arsenic and chromium.
doi:10.1016/j.freeradbiomed.2012.07.020
PMCID: PMC3432141  PMID: 22841757
Metals; histones; hypoxia; oxidative stress; gene expression
16.  Gene Expression Changes in Human Lung Cells Exposed to Arsenic, Chromium, Nickel or Vanadium Indicate the First Steps in Cancer 
The complex process of carcinogenesis begins with transformation of a single cell to favor aberrant traits such as loss of contact inhibition and unregulated proliferation – features found in every cancer. Despite cancer’s widespread prevalence, the early events that initiate cancer remain elusive, and without knowledge of these events cancer prevention is difficult. Here we show that exposure to As, Cr, Ni, or Vanadium (V) promotes changes in gene expression that occur in conjunction with aberrant growth. We exposed immortalized human bronchial epithelial cells to one of four metals/metalloid for four to eight weeks and selected transformed clonal populations based upon anchorage independent growth of single cells in soft agar. We detected a metal-specific footprint of cancer-related gene expression that was consistent across multiple transformed clones. These gene expression changes persisted in the absence of the progenitor metal for numerous cell divisions. Our results show that even a brief exposure to a carcinogenic metal may cause many changes in gene expression in the exposed cells, and that from these many changes, the specific change(s) that each metal causes that initiate cancer likely arise.
doi:10.1039/c2mt20074k
PMCID: PMC3563094  PMID: 22714537
17.  Polo-like Kinase 3 Functions as a Tumor Suppressor and Is a Negative Regulator of Hypoxia-Inducible Factor-1α under Hypoxic Conditions 
Cancer research  2008;68(11):4077-4085.
Polo-like kinase 3 (Plk3) is an important mediator of the cellular responses to genotoxic stresses. In this study, we examined the physiologic function of Plk3 by generating Plk3-deficient mice. Plk3−/− mice displayed an increase in weight and developed tumors in various organs at advanced age. Many tumors in Plk3−/− mice were large in size, exhibiting enhanced angiogenesis. Plk3−/− mouse embryonic fibroblasts were hypersensitive to the induction of hypoxiainducible factor-1α (HIF-1α) under hypoxic conditions or by nickel and cobalt ion treatments. Ectopic expression of the Plk3-kinase domain (Plk3-KD), but not its Polo-box domain or a Plk3-KD mutant, suppressed the nuclear accumulation of HIF-1α induced by nickel or cobalt ions. Moreover, hypoxia-induced HIF-1α expression was tightly associated with a significant down-regulation of Plk3 expression in HeLa cells. Given the importance of HIF-1α in mediating the activation of the “survival machinery” in cancer cells, these studies strongly suggest that enhanced tumorigenesis in Plk3-null mice is at least partially mediated by a deregulated HIF-1 pathway.
doi:10.1158/0008-5472.CAN-07-6182
PMCID: PMC3725591  PMID: 18519666
18.  Carcinogenic Metals and the Epigenome: Understanding the effect of Nickel, Arsenic, and Chromium 
Carcinogenic metals, such as nickel, arsenic, and chromium, are widespread environmental and occupational pollutants. Chronic exposure to these metals has been connected with increased risks of numerous cancers and as well as non-carcinogenic health outcomes, including cardiovascular disease, neurologic deficits, neuro-developmental deficits in childhood, and hypertension. However, currently the specific molecular targets for metal toxicity and carcinogenicity are not fully understood. Here, we propose that the iron- and 2-oxoglutaratedependent dioxygenase family enzymes, as well as, other histone modifying enzymes are important intracellular targets that mediate the toxicity and carcinogenicity of nickel, and maybe potential targets in chromium and arsenic induced carcinogenesis. Our data demonstrates that all three metals are capable of inducing post-translational histone modifications and affecting the enzymes that modulate them (i.e. the iron- and 2-oxoglutaratedependent dioxygenase family, including HIF-prolyl hydroxylase PHD2, histone demethylase JHDM2A/JMJD1A, and DNA repair enzymes ABH3 and ABH2, and histone methyltransferases, G9a). Given the effects these metals can exert on the epigenome, future studies of their involvement in histone modifying enzymes dynamics would deepen our understanding on their respective toxicities and carcinogenicities.
doi:10.1039/c2mt20033c
PMCID: PMC3687545  PMID: 22473328
19.  Nutritionally Mediated Oxidative Stress and Inflammation 
There are many sources of nutritionally mediated oxidative stress that trigger inflammatory cascades along short and long time frames. These events are primarily mediated via NFκB. On the short-term scale postprandial inflammation is characterized by an increase in circulating levels of IL-6 and TNF-α and is mirrored on the long-term by proinflammatory gene expression changes in the adipocytes and peripheral blood mononuclear cells (PBMCs) of obese individuals. Specifically the upregulation of CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CXCL2/MIP-2α, and CXCL3/MIP-2β is noted because these changes have been observed in both adipocytes and PBMC of obese humans. In comparing numerous human intervention studies it is clear that pro-inflammatory and anti-inflammatory consumption choices mediate gene expression in humans adipocytes and peripheral blood mononuclear cells. Arachidonic acid and saturated fatty acids (SFAs) both demonstrate an ability to increase pro-inflammatory IL-8 along with numerous other inflammatory factors including IL-6, TNFα, IL-1β, and CXCL1 for arachidonic acid and IGB2 and CTSS for SFA. Antioxidant rich foods including olive oil, fruits, and vegetables all demonstrate an ability to lower levels of IL-6 in PBMCs. Thus, dietary choices play a complex role in the mediation of unavoidable oxidative stress and can serve to exacerbate or dampen the level of inflammation.
doi:10.1155/2013/610950
PMCID: PMC3697417  PMID: 23844276
20.  THE EFFECT OF EXPOSURE TO CARCINOGENIC METALS ON HISTONE TAIL MODIFICATIONS AND GENE EXPRESSION IN HUMAN SUBJECTS 
The precise mechanisms for the carcinogenesis of nickel and arsenic compounds are not completely understood. In recent years, alterations of epigenetic mechanisms have been implicated in the carcinogenesis of these two metal compounds. In vitro exposure to nickel or arsenic induces changes in both DNA methylation patterns, as well as, in the levels of posttranslational modifications of histone tails. Changes in DNA methylation patterns have been reported in human subjects exposed to arsenic. Here we review our recent reports on the alterations in global levels of posttranslational histone modifications in peripheral blood mononuclear cells (PBMCs) of subjects with occupational exposure to nickel and subjects exposed to arsenic in their drinking water. Occupational exposure to nickel was associated with an increase in H3K4me3 and decrease in H3K9me2. A global increase in H3K9me2 and decrease in H3K9ac was found in subjects exposed to arsenic. Additionally, exposure to arsenic resulted in opposite changes in a number of histone modifications in males compared to females. The results of these two studies suggest that exposure to nickel or arsenic compounds, and possibly other carcinogenic metal compounds, can induce changes in global levels of posttranslational histone modifications in peripheral blood mononuclear cells.
doi:10.1016/j.jtemb.2012.03.012
PMCID: PMC3620044  PMID: 22633395
nickel; arsenic; epigenetics; histone tail modifications
21.  Elucidating the mechanisms of nickel compound uptake: A review of particulate and nano-nickel endocytosis and toxicity 
Nickel (Ni) is a worldwide pollutant and contaminant that humans are exposed to through various avenues resulting in multiple toxic responses - most alarming is its clear carcinogenic nature. A variety of particulate Ni compounds persist in the environment and can be distinguished by characteristics such as solubility, structure, and surface charge. These characteristics influence cellular uptake and toxicity. Some particulate forms of Ni are carcinogenic and are directly and rapidly endocytized by cells. A series of studies conducted in the 1980’s observed this process, and we have reanalyzed the results of these studies to help elucidate the molecular mechanism of particulate Ni uptake. Originally the process of uptake observed was described as phagocytosis, however in the context of recent research we hypothesize that the process is macropinocytosis and/or clathrin mediated endocytosis. Primary considerations in determining the route of uptake here include calcium dependence, particle size, and inhibition through temperature and pharmacological approaches. Particle characteristics that influenced uptake include size, charge, surface characteristics, and structure. This discussion is relevant in the context of nanoparticle studies and the emerging interest in nano-nickel (nano-Ni), where toxicity assessments require a clear understanding of the parameters of particulate uptake and where establishment of such parameters is often obscured through inconsistencies across experimental systems. In this regard, this review aims to carefully document one system (particulate nickel compound uptake) and characterize its properties.
doi:10.1016/j.taap.2011.12.014
PMCID: PMC3306469  PMID: 22206756
macropinocytosis; phagocytosis; clathrin-mediated endocytosis; nickel; nickel sulfide; nickel subsulfide; nanoparticles; toxicity; endocytosis
22.  Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro 
Toxicology and Applied Pharmacology  2011;258(2):166-175.
Hexavalent chromium [Cr(VI)] is a human carcinogen that results in the generation of reactive oxygen species (ROS) and a variety of DNA lesions leading to cell death. Epigallocatechin-3-gallate (EGCG), the major polyphenol present in green tea, possesses potent antioxidative activity capable of protecting normal cells from various stimuli-induced oxidative stress and cell death. Here we demonstrated that co-treatment with EGCG protected human normal bronchial epithelial BEAS-2B cells from Cr(VI)-induced cell death in a dose-dependent manner. Cr(VI) induces apoptosis as the primary mode of cell death. Co-treatment of BEAS-2B cells with EGCG dose-dependently suppressed Cr(VI)-induced apoptosis. Fluorescence microscopic analyses and quantitative measurement revealed that EGCG significantly decreased intracellular levels of ROS induced by Cr(VI) exposure. Using a well-established K+/SDS precipitation assay, we further showed that EGCG was able to dose-dependently reduce DNA-protein cross-links (DPC), lesions that could be partially attributed to Cr(VI)-induced oxidative stress. Finally, analyses of Affymetrix microarray containing 28,869 well-annotated genes revealed that, among the 3412 genes changed more than 1.5-fold by Cr(VI) treatment, changes of 2404 genes (70%) were inhibited by pretreatment of EGCG. Real-time PCR confirmed the induction of 3 genes involved in cell death and apoptosis by Cr(VI), which was eliminated by EGCG. In contrast, Cr(VI) reduced the expression of 3 genes related to cellular defense, and this reduction was inhibited by EGCG. Our results indicate that EGCG protects BEAS-2B cells from Cr(VI)-induced cytotoxicity presumably by scavenging ROS and modulating a subset of genes. EGCG, therefore, might serve as a potential chemopreventive agent against Cr(VI) carcinogenesis.
doi:10.1016/j.taap.2011.10.018
PMCID: PMC3259276  PMID: 22079256
Chromate; EGCG; BEAS-2B cells; Cell death; Apoptosis; Reactive oxygen species; DNA protein cross-links; Gene expression
23.  Histone modifications and cancer: biomarkers of prognosis? 
Epigenetic dysregulation is being increasingly recognized as a hallmark of cancer. Post-translational modifications of histones, in particular, are known to play important roles gene expression alterations in cancer development and progression. Given their key involvement in the various stages of carcinogenesis, histone modifications are also being explored as potential biomarkers of disease progression and prognosis. This review will therefore discuss the role of histone modifications in cancer biology and will explore their prognostic potential.
PMCID: PMC3433108  PMID: 22957310
Histone modifications; cancer; biomarkers; prognosis
24.  XAS Structural Investigation of Early Intermediates in the Mechanism of DNA Repair by Human ABH2 
Biochemistry  2011;50(22):5067-5076.
Human ABH2 repairs DNA lesions by using an Fe(II)- and αKG-dependent oxidative demethylation mechanism. The structure of the active site features the facial triad of protein ligands consisting of the side chains of two histidine and one aspartate residues that is common to many nonheme Fe(II) oxygenases. X-ray absorption spectroscopy (XAS) of metallated (Fe and Ni) samples of ABH2 were used to investigate the mechanism of ABH2 and its inhibition by Ni(II) ions. The data are consistent with a sequential mechanism that features a five coordinate metal center in both the presence and absence of the α-ketoglutarate cofactor. This aspect is not altered in the Ni(II)-substituted enzyme, and both metals are shown to bind the cofactor. When substrate is bound to the native Fe(II) complex with α-ketoglutarate bound, a five-coordinate Fe(II) center is retained that features an open coordination position for O2 binding. However, in the case of the Ni(II)-substituted enzyme, the complex that forms in the presence of cofactor and substrate is six-coordinate, and therefore features no open coordination site for oxygen activation at the metal.
doi:10.1021/bi101668x
PMCID: PMC3124014  PMID: 21510633
25.  Global Levels of Histone Modifications in Peripheral Blood Mononuclear Cells of Subjects with Exposure to Nickel 
Environmental Health Perspectives  2011;120(2):198-203.
Background: Occupational exposure to nickel (Ni) is associated with an increased risk for lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the Ni-induced changes in global histone modification levels have only been tested in vitro.
Objective: This study was conducted in a Chinese population to determine whether occupational exposure to Ni is associated with alterations of global histone modification levels and to evaluate the inter- and intraindividual variance of global histone modification levels.
Method: Forty-five subjects with occupational exposure to Ni and 75 referents were recruited. Urinary Ni and global H3K4 trimethylation, H3K9 acetylation, and H3K9 dimethylation levels were measured in peripheral blood mononuclear cells (PBMCs) of subjects.
Results: H3K4me3 was elevated in Ni-exposed subjects (0.25% ± 0.11%) compared with referents (0.15% ± 0.04%; p = 0.0004), and H3K9me2 was decreased (Ni-exposed subjects, 0.11% ± 0.05%; referents, 0.15% ± 0.04%; p = 0.003). H3K4me3 was positively (r = 0.4, p = 0.0008) and H3K9ac was negatively (r = 0.1, p = 0.01) associated with urinary Ni. Interindividual variances of H3K4me3, H3K9ac, and H3K9me2 were larger compared with intraindividual variance in both exposure test groups, resulting in reliability coefficients (an estimate of consistency of a set of measurements) of 0.60, 0.67, and 0.79 for H3K4me3, H3K9ac, and H3K9me2, respectively, for Ni-exposed subjects and of 0.75, 0.74, and 0.97, respectively, for referent subjects.
Conclusion: The results of this study indicate that occupational exposure to Ni is associated with alterations of global histone modification levels and that measurements of global levels of histone modifications are relatively stable over time in human PBMCs.
doi:10.1289/ehp.1104140
PMCID: PMC3279455  PMID: 22024396
epigenetics; H3K4 trimethylation; H3K9 acetylation; H3K9 dimethylation; histone modifications; interindividual variation; intraindividual variation; nickel; nickel refinery workers

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