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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}
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Li, Shan Hua | - |
dc.contributor.author | Shin, Dong Hoon | - |
dc.contributor.author | Chun, Yang-Sook | - |
dc.contributor.author | Lee, Myung Kyu | - |
dc.contributor.author | Kim, Myung-Suk | - |
dc.contributor.author | Park, Jong-Wan | - |
dc.date.accessioned | 2010-06-25T07:17:30Z | - |
dc.date.available | 2010-06-25T07:17:30Z | - |
dc.date.issued | 2008-12-17 | - |
dc.identifier.citation | Mol Cancer Ther. 2008;7(12):3729-3738 | en |
dc.identifier.issn | 1535-7163 (Print) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19074848 | - |
dc.identifier.uri | http://mct.aacrjournals.org/content/7/12/3729.full.pdf | - |
dc.identifier.uri | https://hdl.handle.net/10371/67830 | - |
dc.description.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. | en |
dc.language.iso | en | en |
dc.publisher | American Association for Cancer Research | en |
dc.subject | Amino Acids, Dicarboxylic/pharmacology | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | Enzyme Activators/*pharmacology | en |
dc.subject | Genes, Reporter | en |
dc.subject | Humans | en |
dc.subject | Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism | en |
dc.subject | Indazoles/chemistry/*pharmacology | en |
dc.subject | Models, Biological | en |
dc.subject | Plasmids/metabolism | en |
dc.subject | Protein Biosynthesis | en |
dc.subject | RNA, Small Interfering/metabolism | en |
dc.subject | Repressor Proteins/*metabolism | en |
dc.subject | Transcriptional Activation | en |
dc.subject | p300-CBP Transcription Factors/*metabolism | en |
dc.subject | Gene Expression Regulation, Neoplastic | - |
dc.title | A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1{alpha} | en |
dc.type | Article | en |
dc.contributor.AlternativeAuthor | 신동훈 | - |
dc.contributor.AlternativeAuthor | 전양숙 | - |
dc.contributor.AlternativeAuthor | 이명규 | - |
dc.contributor.AlternativeAuthor | 김명석 | - |
dc.contributor.AlternativeAuthor | 박종완 | - |
dc.identifier.doi | 10.1158/1535-7163.MCT-08-0074 | - |
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