Hypoxia-inducible factor 1-alpha promoter G-quadruplex DNA (HIF-1α promoter G4 DNA)

The Hypoxia-inducible factor 1-alpha (HIF-1α) promoter G-quadruplex DNA is a non-canonical secondary nucleic acid structure formed within a guanine-rich polypurine/polypyrimidine tract of the HIF1A gene promoter [1, 4]. Located typically between positions -65 and -85 relative to the transcription start site, this G-quadruplex (G4) acts as a critical regulatory element or molecular switch for gene expression [2, 3]. Under both normoxic and hypoxic conditions, the formation and stability of this structure can modulate the binding of transcription factors, such as AP2, and the progression of the transcription machinery [5]. In many solid tumors, HIF-1α is constitutively overexpressed or induced by hypoxia, driving key oncogenic processes including angiogenesis, metabolic reprogramming toward glycolysis, and tumor cell survival [6, 8]. Small molecule ligands, such as CL67, TmPyP4, and telomestatin, have been shown to bind and stabilize the HIF-1α G-quadruplex, leading to the repression of HIF-1α transcription and the subsequent downregulation of its downstream targets like VEGF [1, 4, 6]. Consequently, this DNA structure represents a promising therapeutic target for cancer treatment, offering a way to inhibit the HIF pathway independently of traditional oxygen-dependent degradation mechanisms [1, 10].

Other names

HIF-1α G-quadruplexHIF-1α G4HIF1A promoter G-quadruplexHIF-1α polypurine tract G-quadruplexHypoxia-inducible factor 1-alpha promoter G4 DNA

Stabilization of the G-quadruplex structure within the gene promoter to sterically hinder the transcription machinery and block transcription factor binding, thereby inhibiting gene transcription and subsequent protein expression [1, 5, 6].