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Published August 17, 2007 | Accepted Version + Supplemental Material
Journal Article Open

Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface

Abstract

Transcription mediated by hypoxia-inducible factor (HIF-1) contributes to tumor angiogenesis and metastasis but is also involved in activation of cell-death pathways and normal physiological processes. Given the complexity of HIF-1 signaling, it could be advantageous to target a subset of HIF-1 effectors rather than the entire pathway. We compare the genome-wide effects of three molecules that each interfere with the HIF-1–DNA interaction: a polyamide targeted to the hypoxia response element, small interfering RNA targeted to HIF-1α, and echinomycin, a DNA-binding natural product with a similar but less specific sequence preference than the polyamide. The polyamide affects a subset of hypoxia-induced genes consistent with its binding site preferences. For comparison, HIF-1α siRNA and echinomycin each affect the expression of nearly every gene induced by hypoxia. Remarkably, the total number of genes affected by either polyamide or HIF-1α siRNA over a range of thresholds is comparable. The data show that polyamides can be used to affect a subset of a pathway regulated by a transcription factor. In addition, this study offers a unique comparison of three complementary approaches towards exogenous control of endogenous gene expression.

Additional Information

© 2007 American Chemical Society. Received for review May 18, 2007 and accepted July 26, 2007. Published online August 17, 2007. Accession Codes: Data have been deposited in NCBIs Gene Expression Omnibus (GEO, www.ncbi.nlm.gov/projects/geo), accessible through GEO Series accession number GSE7535.

Attached Files

Accepted Version - nihms277621.pdf

Supplemental Material - cb700110z-file002.pdf

Supplemental Material - cb700110z-file004.pdf

Supplemental Material - cb700110z-file006.pdf

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