Abstract
Homeostasis under hypoxic conditions is maintained through a coordinated transcriptional response mediated by the hypoxia-inducible factor (HIF) pathway and requires coactivation by the CBP and p300 transcriptional coactivators. Through a target-based high-throughput screen, we identified chetomin as a disrupter of HIF binding to p300. At a molecular level, chetomin disrupts the structure of the CH1 domain of p300 and precludes its interaction with HIF, thereby attenuating hypoxia-inducible transcription. Systemic administration of chetomin inhibited hypoxia-inducible transcription within tumors and inhibited tumor growth. These results demonstrate a therapeutic window for pharmacological attenuation of HIF activity and further establish the feasibility of disrupting a signal transduction pathway by targeting the function of a transcriptional coactivator with a small molecule.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Anti-Bacterial Agents / pharmacology*
-
Aryl Hydrocarbon Receptor Nuclear Translocator
-
Carcinoma, Hepatocellular / pathology
-
Cell Hypoxia / genetics
-
Colonic Neoplasms / metabolism
-
Colonic Neoplasms / pathology
-
Colonic Neoplasms / therapy
-
DNA-Binding Proteins*
-
Disulfides
-
E1A-Associated p300 Protein
-
Erythropoietin / metabolism
-
Humans
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Indole Alkaloids
-
Liver Neoplasms / pathology
-
Luciferases / metabolism
-
Male
-
Mice
-
Mice, Nude
-
Nuclear Proteins / genetics
-
Nuclear Proteins / metabolism*
-
Prostatic Neoplasms / metabolism
-
Prostatic Neoplasms / pathology
-
Prostatic Neoplasms / therapy
-
Protein Binding / drug effects
-
Receptors, Aryl Hydrocarbon / genetics
-
Receptors, Aryl Hydrocarbon / metabolism*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Trans-Activators / genetics
-
Trans-Activators / metabolism*
-
Transcription Factors / genetics
-
Transcription Factors / metabolism*
-
Transcription, Genetic / drug effects*
-
Transplantation, Heterologous
-
Vascular Endothelial Growth Factor A / metabolism
Substances
-
ARNT protein, human
-
Anti-Bacterial Agents
-
Arnt protein, mouse
-
DNA-Binding Proteins
-
Disulfides
-
HIF1A protein, human
-
Hypoxia-Inducible Factor 1, alpha Subunit
-
Indole Alkaloids
-
Nuclear Proteins
-
Receptors, Aryl Hydrocarbon
-
Trans-Activators
-
Transcription Factors
-
Vascular Endothelial Growth Factor A
-
Erythropoietin
-
Aryl Hydrocarbon Receptor Nuclear Translocator
-
chetomin
-
Luciferases
-
E1A-Associated p300 Protein
-
Ep300 protein, mouse