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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Science Applications International Corporation-Frederick, Inc., and 2 Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute at Frederick, Frederick, Maryland
Requests for reprints: Giovanni Melillo, Developmental Therapeutics Program, Tumor Hypoxia Laboratory, National Cancer Institute at Frederick, Building 432, Room 218, Frederick, MD 21702. Phone: 301-846-5050; Fax: 301-846-6081; E-mail: melillog{at}ncifcrf.gov.
The identification of small molecules that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1
and HIF-1ß proteins containing the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1 and HIF-1ß proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1–targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a small-molecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1 and HIF-1ß proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-
B (NF-B) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-B to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.
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