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

The Hypoxia-inducible factor 2-alpha (HIF-2α) promoter G-quadruplex is a non-canonical DNA secondary structure located within the guanine-rich regulatory region of the EPAS1 gene [1.2.1]. This structure consists of stacked guanine tetrads stabilized by Hoogsteen hydrogen bonding and monovalent cations, serving as a critical molecular switch for transcriptional control [1.2.3, 1.2.5]. In oncogenic contexts, particularly in clear cell renal cell carcinoma (ccRCC) and neuroblastoma, HIF-2α is frequently overexpressed, driving angiogenesis, metabolism, and cell survival [1.2.1, 1.3.2]. The G-quadruplex structure in its promoter acts as a transcriptional silencer; when stabilized by small-molecule ligands, it physically obstructs the assembly of the transcription initiation complex and the binding of activating transcription factors such as Sp1 [1.2.1, 1.4.2]. Consequently, targeting this structure with G-quadruplex-stabilizing drugs like CL67 or TMPyP4 offers a therapeutic strategy to downregulate HIF-2α expression at the genomic level [1.2.1, 1.4.3]. This approach is particularly relevant for treating cancers that are resistant to traditional therapies or where the HIF-2α protein itself is difficult to inhibit directly [1.2.1, 1.4.1].

Other names

EPAS1 promoter G-quadruplexHIF2A promoter G-quadruplexG-quadruplex structures in the EPAS1 promoterHIF-2α G4

Stabilization of the G-quadruplex structure within the promoter region of the EPAS1 gene, which inhibits the binding of transcription factors (e.g., Sp1, AP2) and the assembly of the RNA polymerase II complex, thereby repressing the transcription of HIF-2α [1.2.1, 1.4.3].