Hypoxia-inducible factor 2-alpha promoter G-quadruplex DNA (HIF-2α promoter G4 DNA)

The Hypoxia-inducible factor 2-alpha (HIF-2α) promoter G-quadruplex DNA is a non-canonical secondary structure found in the regulatory region of the EPAS1 gene [1]. This structure consists of guanine-rich sequences that fold into four-stranded arrangements stabilized by Hoogsteen hydrogen bonds and monovalent cations [5, 7]. It serves as a critical regulatory element that modulates the transcription of HIF-2α, a protein essential for the cellular response to low oxygen levels [1, 8]. In many cancers, particularly clear cell renal cell carcinoma, HIF-2α is overexpressed due to the loss of the von Hippel-Lindau (VHL) tumor suppressor, driving angiogenesis and tumor growth [1, 8]. The G-quadruplex structure in the promoter acts as a molecular switch; its formation or stabilization typically leads to the repression of gene transcription [1, 5]. Small molecule ligands, such as the naphthalene derivative CL67 and the porphyrin TMPyP4, have been shown to bind and stabilize this specific G-quadruplex [1, 9]. By stabilizing the structure, these ligands prevent the assembly of the transcriptional machinery, thereby reducing the levels of HIF-2α mRNA and protein [1]. This mechanism represents a promising therapeutic strategy to target transcription factors at the genomic level [5, 6]. However, achieving high selectivity for the HIF-2α G-quadruplex over other genomic G-quadruplexes remains a significant challenge in drug development [5, 9]. Research into this target continues to expand the potential for precision oncology by focusing on DNA secondary structures as therapeutic vulnerabilities [10].

Other names

EPAS1 promoter G-quadruplexHIF2A promoter G4G-quadruplex in the HIF-2α promoterHIF-2-alpha promoter G-quadruplex

Stabilization of the G-quadruplex structure within the promoter region of the EPAS1 gene to inhibit the binding of the transcriptional machinery and repress gene expression [1, 5].