SRY-box transcription factor 2 (SOX2) promoter G-quadruplex and i-motif region (SOX2 promoter G4/i-motif)

The SRY-box transcription factor 2 (SOX2) promoter contains a nuclease hypersensitive element (NHE) with a G-rich sequence homologous to the c-MYC Pu27 region, which is capable of folding into G-quadruplex (G4) structures (Source: Scientific Reports 2017;7:10138). The complementary C-rich strand of this region can also form i-motif structures, which serve as additional regulatory switches for gene expression (Source: Bioorg Med Chem Lett 2018;28:1518). These non-canonical DNA structures play a critical role in regulating the transcription of SOX2, a master transcription factor essential for maintaining the pluripotency and self-renewal of embryonic and cancer stem cells (Source: UniProt P48431). SOX2 is frequently overexpressed in aggressive malignancies, including glioblastoma and lung cancer, where it drives tumor progression and resistance to therapy (Source: PubMed 28844886). Small molecule ligands that stabilize these G4 or i-motif structures can effectively downregulate SOX2 expression, offering a therapeutic strategy to target cancer stemness and overcome chemoresistance (Source: Nucleic Acids Res 2014;42:7422). However, achieving high selectivity for the SOX2-specific sequence over other genomic G-quadruplexes remains a significant challenge in drug development (Source: PubMed 30245445).

Other names

SOX2 promoter Pu27-homologous regionSOX2 G-quadruplexSOX2 i-motifSOX2 nuclease hypersensitive elementSOX2 NHE

Stabilization of G-quadruplex or i-motif structures within the SOX2 promoter to sterically hinder transcription factor binding and RNA polymerase recruitment, leading to transcriptional repression of the SOX2 gene.