Vascular endothelial growth factor A promoter (VEGFA promoter) (VEGFA promoter)

The Vascular endothelial growth factor A (VEGFA) promoter is a regulatory DNA sequence located upstream of the VEGFA gene that serves as the primary control point for the expression of the VEGF protein. This promoter is characterized by its complexity, containing multiple binding sites for transcription factors such as Sp1, AP-1, and Hypoxia-Inducible Factor 1 (HIF-1), the latter of which binds to a specific Hypoxia Response Element (HRE) during low-oxygen conditions (Forsythe et al., 1996, Mol. Cell. Biol.). A notable feature of the VEGF promoter is its ability to form G-quadruplex (G4) secondary structures within its GC-rich regions, which can naturally modulate transcription (Sun et al., 2005, J. Am. Chem. Soc.). In various cancers and neovascular diseases, the promoter is hyperactivated, leading to the overproduction of VEGF and subsequent pathological angiogenesis. Pharmacological targeting of the VEGF promoter involves the use of small molecules, such as APTO-253, designed to stabilize these G-quadruplexes or interfere with transcription factor recruitment (Aptose Biosciences). By stabilizing the G4 structure, drugs can effectively lock the promoter in a state that prevents the transcriptional machinery from proceeding. This transcriptional silencing approach is being explored to overcome resistance associated with traditional anti-VEGF protein-targeting therapies by reducing the total pool of VEGF protein available in the microenvironment.

Other names

VEGF promoterVEGF-A promoterVascular endothelial growth factor promoterVEGFA regulatory region

Inhibition of gene transcription through the stabilization of G-quadruplex (G4) DNA structures or competitive binding to GC-rich promoter regions, which prevents the recruitment of transcription factors such as Sp1 and Hypoxia-Inducible Factor 1-alpha (HIF-1α).