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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}

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dc.contributor.authorLi, Shan Hua-
dc.contributor.authorShin, Dong Hoon-
dc.contributor.authorChun, Yang-Sook-
dc.contributor.authorLee, Myung Kyu-
dc.contributor.authorKim, Myung-Suk-
dc.contributor.authorPark, Jong-Wan-
dc.date.accessioned2010-07-01T07:09:34Z-
dc.date.available2010-07-01T07:09:34Z-
dc.date.issued2008-12-17-
dc.identifier.citationMol Cancer Ther. 2008;7(12):3729-3738en
dc.identifier.issn1535-7163 (Print)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19074848-
dc.identifier.urihttp://mct.aacrjournals.org/content/7/12/3729.full.pdf-
dc.identifier.urihttps://hdl.handle.net/10371/68163-
dc.description.abstractHypoxia-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.en
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.subjectAmino Acids, Dicarboxylic/pharmacologyen
dc.subjectCell Line, Tumoren
dc.subjectEnzyme Activators/*pharmacologyen
dc.subject*Gene Expression Regulation, Neoplasticen
dc.subjectGenes, Reporteren
dc.subjectHumansen
dc.subjectHypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolismen
dc.subjectIndazoles/chemistry/*pharmacologyen
dc.subjectModels, Biologicalen
dc.subjectPlasmids/metabolismen
dc.subjectProtein Biosynthesisen
dc.subjectRNA, Small Interfering/metabolismen
dc.subjectRepressor Proteins/*metabolismen
dc.subjectTranscriptional Activationen
dc.subjectp300-CBP Transcription Factors/*metabolismen
dc.titleA novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha}en
dc.typeArticleen
dc.contributor.AlternativeAuthor신동훈-
dc.contributor.AlternativeAuthor전양숙-
dc.contributor.AlternativeAuthor이명규-
dc.contributor.AlternativeAuthor김명석-
dc.contributor.AlternativeAuthor박종완-
dc.identifier.doi10.1158/1535-7163.MCT-08-0074-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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