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CITED2 mediates the paradoxical responses of HIF-1α to proteasome inhibition

Oncogene volume 27, pages 1939–1944 (2008)Cite this article

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is destabilized via the ubiquitin–proteasome system. Thus HIF-1α expression is robustly upregulated by proteasome inhibition, but paradoxically its activity is reduced. In the present study, we investigated the mechanism underlying the paradoxical response of HIF-1α to proteasome inhibition. In both Hep3B and HEK293 cells, a proteasome inhibitor MG132 noticeably attenuated hypoxic induction of erythropoietin and VEGF mRNAs. MG132 inactivated HIF-1α C-terminal transactivation domain (CAD), independently of factor inhibiting HIF-1 (FIH) and inhibited p300 recruitment by HIF-1α. We next tested the possibility that CITED2 is involved in the HIF-1 inactivation. CITED2 was found to be degraded via the ubiquitin–proteasome system and thus was stabilized by proteasome inhibition. Both the activity and the p300 binding of HIF-1α were inhibited by CITED2 expression and recovered by CITED2 siRNA in the presence of MG132. These results suggest that CITED2 is stabilized by proteasome inhibition and inactivates HIF-1 by interfering with the HIF-1α–p300 interaction. This may be an important mode-of-action for proteasome inhibition-based cancer therapy.

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Acknowledgements

This work was supported by a grant from The National R&D Program for Cancer Control, Korean Ministry of Health & Welfare Research Fund (no. 0520260-2).

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  1. D H Shin and S H Li: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, Korea

    D H Shin, S H Li, M-S Kim & J-W Park

  2. Department of Physiology and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, Korea

    Y-S Chun

  3. Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, USA

    L E Huang

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  1. D H Shin
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Correspondence to J-W Park.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Shin, D., Li, S., Chun, YS. et al. CITED2 mediates the paradoxical responses of HIF-1α to proteasome inhibition. Oncogene 27, 1939–1944 (2008). https://doi.org/10.1038/sj.onc.1210826

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