| Elevated SP-1 transcription factor expression and activity drives basal and hypoxia-induced vascular endothelial growth factor (VEGF) expression in non-small cell lung cancer. | |
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MedLine Citation:
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PMID: 22992725 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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VEGF plays a central role in angiogenesis in cancer. Non-small cell lung cancer (NSCLC) tumors have increased microvascular density, localized hypoxia, and high VEGF expression levels; however, there is a lack of understanding of how oncogenic and tumor microenvironment changes such as hypoxia lead to greater VEGF expression in lung and other cancers. We show that NSCLC cells secreted higher levels of VEGF than normal airway epithelial cells. Actinomycin D inhibited all NSCLC VEGF secretion, and VEGF minimal promoter-luciferase reporter constructs were constitutively active until the last 85 base pairs before the transcription start site containing three SP-1 transcription factor-binding sites; mutation of these VEGF promoter SP-1-binding sites eliminated VEGF promoter activity. Furthermore, dominant negative SP-1, mithramycin A, and SP-1 shRNA decreased VEGF promoter activity, whereas overexpression of SP-1 increased VEGF promoter activity. Chromatin immunoprecipitation assays demonstrated SP-1, p300, and PCA/F histone acetyltransferase binding and histone H4 hyperacetylation at the VEGF promoter in NSCLC cells. Cultured NSCLC cells expressed higher levels of SP-1 protein than normal airway epithelial cells, and double-fluorescence immunohistochemistry showed a strong correlation between SP-1 and VEGF in human NSCLC tumors. In addition, hypoxia-driven VEGF expression in NSCLC cells was SP-1-dependent, with hypoxia increasing SP-1 activity and binding to the VEGF promoter. These studies are the first to demonstrate that overexpression of SP-1 plays a central role in hypoxia-induced VEGF secretion. |
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Authors:
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Karl Deacon; David Onion; Rajendra Kumari; Susan A Watson; Alan J Knox |
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Publication Detail:
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Type: Clinical Trial; Journal Article Date: 2012-09-18 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-19 Completed Date: 2013-02-19 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 39967-81 Citation Subset: IM |
Affiliation:
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Centre for Respiratory Research, University of Nottingham, Nottingham, NG5 1PB, United Kingdom. karl.deacon@nottingham.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Anoxia
/
genetics,
metabolism*,
pathology Carcinoma, Non-Small-Cell Lung / blood supply*, genetics, metabolism*, pathology Cell Hypoxia Cell Line, Tumor Dactinomycin / pharmacology Female Gene Expression Regulation, Neoplastic* Histones / genetics, metabolism Humans Lung Neoplasms / blood supply*, genetics, metabolism*, pathology Male Neoplasm Proteins / biosynthesis*, genetics Neovascularization, Pathologic / genetics, metabolism, pathology Nucleic Acid Synthesis Inhibitors / pharmacology Promoter Regions, Genetic / genetics Protein Binding Sp1 Transcription Factor / biosynthesis*, genetics Vascular Endothelial Growth Factor A / biosynthesis*, genetics p300-CBP Transcription Factors / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Histones; 0/Neoplasm Proteins; 0/Nucleic Acid Synthesis Inhibitors; 0/Sp1 Transcription Factor; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; 50-76-0/Dactinomycin; EC 2.3.1.48/p300-CBP Transcription Factors; EC 2.3.1.48/p300-CBP-associated factor |
| Comments/Corrections | |
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