Faculty Bibliography

Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell cycle G0/G1 arrest as well as down-regulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In current studies, the potential ISO inhibition of bladder tumor formation has been explored in xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anti-cancer activities has been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by direct targeting Sp1 mRNA 3'UTR. Similar to ISO treatment, ectopic expression of miR-137 alone led to G0/G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by over-expression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced the inhibition of Sp1/Cyclin D1 expression, and induction of G0/G1 cell growth arrest and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3'UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0/G1 growth arrest and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anti-cancer activity of ISO in the therapy of human bladder cancer.

The special AT-rich sequence-binding protein 2 (SATB2) is a protein that binds to the nuclear matrix attachment region of the cell and regulates gene expression by altering chromatin structure. In our previous study, we reported that SATB2 gene expression was induced in human bronchial epithelial BEAS-2B cells transformed by arsenic, chromium, nickel and vanadium. In this study, we show that ectopic expression of SATB2 in the normal human bronchial epithelial cell-line BEAS-2B increased anchorage-independent growth and cell migration, meanwhile, shRNA-mediated knockdown of SATB2 significantly decreased anchorage-independent growth in Ni transformed BEAS-2B cells. RNA sequencing analyses of SATB2 regulated genes revealed the enrichment of those involved in cytoskeleton, cell adhesion and cell-movement pathways. Our evidence supports the hypothesis that SATB2 plays an important role in BEAS-2B cell transformation.

Oxygen levels range from 2-9% in vivo. Atmospheric O2 levels (21%) are known to induce cell proliferation defects and cellular senescence in primary cell cultures. However, the mechanistic basis of the deleterious effects of higher O2 levels is not fully understood. On the other hand, immortalized cells including cancer cell lines, which evade cellular senescence are normally cultured at 21% O2 and the effects of higher O2 on these cells are understudied. Here we addressed this problem by culturing immortalized human bronchial epithelial (BEAS-2B) cells at ambient atmospheric, 21% O2 and lower, 10% O2 . Our results show increased inflammatory response at 21% O2 but not at 10% O2 . We found higher RelA binding at the NF-kappaB1/RelA target gene promoters as well as upregulation of several pro-inflammatory cytokines in cells cultured at 21% O2 . RelA knockdown prevented the upregulation of the pro-inflammatory cytokines at 21% O2 , suggesting NF-kappaB1/RelA as a major mediator of inflammatory response in cells cultured at 21% O2 . Interestingly, unlike the 21% O2 cultured cells, exposure of 10% O2 cultured cells to H2 O2 did not elicit inflammatory response, suggesting increased ability to tolerate oxidative stress in cells cultured at lower O2 levels

MOF was first identified in Drosophila melanogaster as an important component of the dosage compensation complex. As a member of MYST family of histone acetyltransferase, MOF specifically deposits the acetyl groups to histone H4 lysine 16. Throughout evolution, MOF and its mammalian ortholog have retained highly conserved substrate specificity and similar enzymatic activities. MOF plays important roles in dosage compensation, ESC self-renewal, DNA damage and repair, cell survival, and gene expression regulation. Dysregulation of MOF has been implicated in tumor formation and progression of many types of human cancers. This review will discuss the structure and activity of mammalian hMOF as well as its function in H4K16 acetylation, DNA damage response, stem cell pluripotency, and carcinogenesis.

Particulate matter (PM) exposures have been linked to mortality, low birth weights, hospital admissions, and diseases associated with metabolic syndrome, including diabetes mellitus, cardiovascular disease, and obesity. In a previous in vitro and in vivo study, data demonstrated that PM10mum collected from Jeddah, Saudi Arabia (PMSA), altered expression of genes involved in lipid and cholesterol metabolism, as well as many other genes associated with metabolic disorders. PMSA contains a relatively high concentration of nickel (Ni), known to be linked to several metabolic disorders. In order to evaluate whether Ni and PM exposures induce similar gene expression profiles, mice were exposed to 100 mug/50 mul PMSA (PM-100), 50 mug/50 mul nickel chloride (Ni-50), or 100 mug/50 mul nickel chloride (Ni-100) twice per week for 4 wk and hepatic gene expression changes were determined. Ultimately, 55 of the same genes were altered in all 3 exposures. However, where the two Ni groups differed markedly was in the regulation (up or down) of these genes. Ni-100 and PM-100 groups displayed similar regulations, whereby 104 of the 107 genes were similarly modulated. Many of the 107 genes are involved in metabolic syndrome and include ALDH4A1, BCO2, CYP1A, CYP2U, TOP2A. In addition, the top affected pathways, such as fatty acid alpha-oxidation, and lipid and carbohydrate metabolism, are involved in metabolic diseases. Most notably, the top diseased outcome affected by these changes in gene expression was cardiovascular disease. Given these data, it appears that Ni and PMSA exposures display similar gene expression profiles, modulating the expression of genes involved in metabolic disorders.

Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the Earth's crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0muM Cd for 24h; or chronically-treated with 0.01, 0.05, or 0.1muM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip(R) Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24h indicated a reduction in global levels of histone methylation and acetylation that persisted 72h post-treatment.

Hexavalent chromium [Cr(VI)] is a known carcinogen when inhaled. However, inhalational exposure to Cr(VI) affects only a small portion of the population, mainly by occupational exposures. In contrast, oral exposure to Cr(VI) is widespread and affects many people throughout the globe. In 2008, the National Toxicology Program (NTP) released a 2-year study demonstrating that ingested Cr(VI) was carcinogenic in rats and mice. The effects of Cr(VI) oral exposure are mitigated by reduction in the gut; however, a portion evades the reductive detoxification and reaches target tissues. Once Cr(VI) enters the cell, it ultimately gets reduced to Cr(III), which mediates its toxicity via induction of oxidative stress during the reduction while Cr intermediates react with protein and DNA. Cr(III) can form adducts with DNA that may lead to mutations. This review will discuss the potential adverse effects of oral exposure to Cr(VI) by presenting up-to-date human and animal studies, examining the underlying mechanisms that mediate Cr(VI) toxicity, as well as highlighting opportunities for future research.

Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten (W), remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. Here, for the first time, we demonstrate tungsten's ability to induce carcinogenic related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer-related pathways in transformed clones as determined by RNA sequencing. Human bronchial epithelial cell line (Beas-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA-sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. Taken together, our data show the carcinogenic potential of tungsten. Further tests are needed, including in vivo and human studies, in order to validate tungsten as a carcinogen to humans.

The replication-dependent histone genes are the only metazoan genes whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3' end. Instead, the histone mRNAs display a stem-loop structure at their 3' end. Stem-loop binding protein (SLBP) binds the stem-loop and regulates canonical histone mRNA metabolism. Here we report that exposure to arsenic, a carcinogenic metal, decreases cellular levels of SLBP by inducing its proteasomal degradation and inhibiting SLBP transcription via epigenetic mechanisms. Notably, arsenic exposure dramatically increases polyadenylation of canonical histone H3.1 mRNA possibly through downregulation of SLBP expression. The polyadenylated H3.1 mRNA induced by arsenic is not susceptible to normal degradation that occurs at the end of S phase, resulting in continued presence into mitosis, increased total H3.1 mRNA, and increased H3 protein levels. Excess expression of canonical histones has been shown to increase sensitivity to DNA damage, as well as increase the frequency of missing chromosomes and induce genomic instability. Thus, polyadenylation of canonical histone mRNA following arsenic exposure may contribute to arsenic-induced carcinogenesis.