SATB2 is a homobox transcription factor first discovered in 2003 that binds to AT rich sequences and likely binds chromatin modifying enzymes such as histone acetyltranferases and deacetylases for the regulation of gene expression. A number of recent papers have described SATB2 overexpression in a variety of cancers and have emphasized the importance of this overexpressed gene in driving tumorigenesis. We have studied the malignant transformation of normal human bronchial epithelial cells (BEAS2B) by carcinogenic metals such as nickel (Ni), hexavalent chromium (Cr+6), arsenic (As) and vanadate (V). While each of these metals has its own unique signature of gene expression when they transform BEAS2B cells, the signature is vastly different from metal to metal. However, SATB2 is increased in every transformed clone by any one of these metals. SATB2 is not expressed in parental BEAS2B cells. Further studies have shown that SATB2 mRNA and protein are induced in BEAS2B cells by chronic Ni ion treatment. We hypothesize that SATB2 is a transcription factor needed for normal mammalian development but its inappropriate expression during chronic Ni exposure is a driver of cell transformation. We want to investigate the mechanisms and consequences of its overexpression in BEAS2B and 16HB cells exposed to and transformed by Ni. We will overexpress SATB2 in normal BEAS-2B and 16HBE cells and investigate the effect this has on the cell's transformed properties and study the expression of other genes in these cells using gene chips. SATB2 overexpression and resulting cell transformation will also be studied in the presence of nickel exposure. We will lower the levels of SATB2 by transient knockdown with siRNA and stable knockdown with small hairpin RNA in nickel transformed BEAS2B and 16HBE cells and study the consequences of SATB2 loss on their transformed properties and investigate the effect this knockdown has on the expression of other genes using gene chips in the nickel transformed cells. We will study the mechanism of SATB2 overexpression focusing on its promoter, enhancer, upstream regulators and miRNA that target SATB2 following chronic nickel treatment of BEAS2B and 16HBE cells and in nickel transformed cells. In addition, SATB2 overexpressed in BEAS2B and 16HBE cells and in Ni-transformed cells will be immunoprecipitated, and interacting protein partners will be identified by gel electrophoresis and mass spectrometry. To address whether nickel is able to induce SATB2 expression in vivo, we will expose A/J mice to various doses of nickel by inhalation or ingestion, and analyze SATB2 expression in several target tissues. To explore the role of SATB2 in nickel-induced tumorigenesis, we will analyze the levels of SATB2 expression in rat lung tumors induced by nickel subsulfide exposure (obtained from National Toxicology Program archive).

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-DKUS-C (90))
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Tyson, Frederick L
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New York University
Public Health & Prev Medicine
Schools of Medicine
New York
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Chen, Qiao Yi; Costa, Max (2018) PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis. Mol Pharmacol 94:784-792
Jordan, Ashley; Zhang, Xiaoru; Li, Jinquan et al. (2017) Nickel and cadmium-induced SLBP depletion: A potential pathway to metal mediated cellular transformation. PLoS One 12:e0173624
Laulicht-Glick, Freda; Wu, Feng; Zhang, Xiaoru et al. (2017) Tungsten exposure causes a selective loss of histone demethylase protein. Mol Carcinog 56:1778-1788
Jagannathan, Lakshmanan; Cuddapah, Suresh; Costa, Max (2016) Oxidative stress under ambient and physiological oxygen tension in tissue culture. Curr Pharmacol Rep 2:64-72
Cartularo, Laura; Kluz, Thomas; Cohen, Lisa et al. (2016) Molecular Mechanisms of Malignant Transformation by Low Dose Cadmium in Normal Human Bronchial Epithelial Cells. PLoS One 11:e0155002
Wu, Feng; Jordan, Ashley; Kluz, Thomas et al. (2016) SATB2 expression increased anchorage-independent growth and cell migration in human bronchial epithelial cells. Toxicol Appl Pharmacol 293:30-6
Chen, Danqi; Kluz, Thomas; Fang, Lei et al. (2016) Hexavalent Chromium (Cr(VI)) Down-Regulates Acetylation of Histone H4 at Lysine 16 through Induction of Stressor Protein Nupr1. PLoS One 11:e0157317
Jagannathan, Lakshmanan; Jose, Cynthia C; Arita, Adriana et al. (2016) Nuclear Factor ?B1/RelA Mediates Inflammation in Human Lung Epithelial Cells at Atmospheric Oxygen Levels. J Cell Physiol 231:1611-20
Niu, Yingmei; DesMarais, Thomas L; Tong, Zhaohui et al. (2015) Oxidative stress alters global histone modification and DNA methylation. Free Radic Biol Med 82:22-8
Laulicht, Freda; Brocato, Jason; Cartularo, Laura et al. (2015) Tungsten-induced carcinogenesis in human bronchial epithelial cells. Toxicol Appl Pharmacol 288:33-9

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