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A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}

Cited 92 time in Web of Science Cited 105 time in Scopus
Authors
Li, Shan Hua; Shin, Dong Hoon; Chun, Yang-Sook; Lee, Myung Kyu; Kim, Myung-Suk; Park, Jong-Wan
Issue Date
2008-12-17
Publisher
American Association for Cancer Research
Citation
Mol Cancer Ther. 2008;7(12):3729-3738
Keywords
Amino Acids, Dicarboxylic/pharmacologyCell Line, TumorEnzyme Activators/*pharmacology*Gene Expression Regulation, NeoplasticGenes, ReporterHumansHypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolismIndazoles/chemistry/*pharmacologyModels, BiologicalPlasmids/metabolismProtein BiosynthesisRNA, Small Interfering/metabolismRepressor Proteins/*metabolismTranscriptional Activationp300-CBP Transcription Factors/*metabolism
Abstract
Hypoxia-inducible factor (HIF)-1 plays a key role in tumor promotion by inducing approximately 60 genes required for tumor adaptation to hypoxia; thus, it is viewed as a target for cancer therapy. For this reason, YC-1, which down-regulates HIF-1alpha and HIF-2alpha at the post-translational level, is being developed as a novel anticancer drug. We here found that YC-1 acts in a novel manner to inhibit HIF-1. In the Gal4 reporter system, which is not degraded by YC-1, YC-1 was found to significantly inactivate the COOH-terminal transactivation domain (CAD) of HIF-1alpha, whereas it failed to inactivate CAD(N803A) mutant. In coimmunoprecipitation assays, YC-1 stimulated factor inhibiting HIF (FIH) binding to CAD even in hypoxia, whereas it failed to increase the cellular levels of hydroxylated Asn803 of CAD. It was also found that YC-1 prevented p300 recruitment by CAD in mammalian two-hybrid and coimmunoprecipitation assays. The involvement of FIH in YC-1-induced CAD inactivation was confirmed in EPO-enhancer and Gal4 reporter systems using FIH small interfering RNA and dimethyloxalylglycine FIH inhibitor. Indeed, FIH inhibition rescued HIF target gene expressions repressed by YC-1. In cancer cell lines other than Hep3B, YC-1 inhibits HIF-1alpha via the FIH-dependent CAD inactivation as well as via the protein down-regulation. Given these results, we suggest that the functional inactivation of HIF-alpha contributes to the YC-1-induced deregulation of hypoxia-induced genes.
ISSN
1535-7163 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19074848

http://mct.aacrjournals.org/content/7/12/3729.full.pdf

http://hdl.handle.net/10371/68163
DOI
https://doi.org/10.1158/1535-7163.MCT-08-0074
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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