Exploring the formation and recognition of an important G-quadruplex in a HIF1α promoter and its transcriptional inhibition by a benzo[c]phenanthridine derivative.
Four putative G-quadruplex sequences (PGSs) in the HIF1α promoter and the 5'UTR were evaluated for their G-quadruplex-forming potential using ESI-MS, CD, FRET, DMS footprinting, and a polymerase stop assay. An important G-quadruplex (S1) has been proven to inhibit HIF1α transcription by blocking AP2 binding. A benzo[c]phenanthridine derivative was found to target the S1 G-quadruplex and induce its conformational conversion from antiparallel to parallel orientation. The transcriptional suppression of HIF1α by this compound was demonstrated using western blotting, Q-RT-PCR, luciferase assay, and ChIP. Our new findings provided a novel strategy for HIF1α regulation and potential insight for cancer therapy.
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University , Beijing 100871, China.
Han
H
Chen
Haitao
H
Long
Xiaojie
X
Cui
Jiang
J
Zhou
Ming
M
Xu
Gu
G
Yuan
D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D015153:Blotting, Western; D002942:Circular Dichroism; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008958:Models, Molecular; D010617:Phenanthridines / Q000737:chemistry* / Q000494:pharmacology; D011401:Promoter Regions, Genetic
D001565:Benzoates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010617:Phenanthridines; C009852:benzoyl bromide