Document Detail


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.
MedLine Citation:
PMID:  22992725     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Karl Deacon; David Onion; Rajendra Kumari; Susan A Watson; Alan J Knox
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Publication Detail:
Type:  Clinical Trial; Journal Article     Date:  2012-09-18
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-02-19     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  39967-81     Citation Subset:  IM    
Affiliation:
Centre for Respiratory Research, University of Nottingham, Nottingham, NG5 1PB, United Kingdom. karl.deacon@nottingham.ac.uk
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MeSH Terms
Descriptor/Qualifier:
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:
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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