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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES022935-01A1
Application #
8685083
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Tyson, Frederick L
Project Start
2014-05-01
Project End
2019-01-31
Budget Start
2014-05-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$381,375
Indirect Cost
$156,375
Name
New York University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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
Jagannathan, Lakshmanan; Jose, Cynthia C; Arita, Adriana et al. (2016) Nuclear Factor κB1/RelA Mediates Inflammation in Human Lung Epithelial Cells at Atmospheric Oxygen Levels. J Cell Physiol 231:1611-20
Cartularo, Laura; Laulicht, Freda; Sun, Hong et al. (2015) Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium. Toxicol Appl Pharmacol 288:399-408
Brocato, Jason; Costa, Max (2015) SATB1 and 2 in colorectal cancer. Carcinogenesis 36:186-91
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
Brocato, Jason; Chen, Danqi; Liu, Jianli et al. (2015) A Potential New Mechanism of Arsenic Carcinogenesis: Depletion of Stem-Loop Binding Protein and Increase in Polyadenylated Canonical Histone H3.1 mRNA. Biol Trace Elem Res 166:72-81
Sun, Hong; Brocato, Jason; Costa, Max (2015) Oral Chromium Exposure and Toxicity. Curr Environ Health Rep 2:295-303
Brocato, Jason; Wu, Fen; Chen, Yu et al. (2015) Association between sleeping hours and cardiometabolic risk factors for metabolic syndrome in a Saudi Arabian population. BMJ Open 5:e008590
Muñoz, Alexandra; Chervona, Yana; Hall, Megan et al. (2015) Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water. Toxicol Appl Pharmacol 284:330-8

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