A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1alpha = HIF 억제에 있어서 YC-1의 새로운 활성 모드

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Title
A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1alpha = HIF 억제에 있어서 YC-1의 새로운 활성 모드
Author(s)
S H Li; D H Shin; Y S Chun; Myung Kyu Lee; M S Kim; J W Park
Bibliographic Citation
Molecular Cancer Therapeutics, vol. 7, no. 12, pp. 3729-3738
Publication Year
2008
Abstract
Hypoxia-inducible factor (HIF)-1 plays a key role in tumor promotion by inducing ∼60 genes required for tumor adaptation to hypoxia; thus, it is viewed as a target for cancer therapy. For this reason, YC-1, which downregulates HIF-1α and HIF-2α 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-1α, 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-1α 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-α contributes to the YC-1-induced deregulation of hypoxia-induced genes.
ISSN
1535-7163
Publisher
Amer Assoc Cancer Research
DOI
http://dx.doi.org/10.1158/1535-7163.MCT-08-0074
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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