1. Histone Deacetylase Inhibitors Induce VHL and Ubiquitin-Independent Proteasomal Degradation of Hypoxia-Inducible Factor 1α
- Author
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Nianli Sang, Jaime Caro, Dongming Liang, Donna M. Fath, Xianguo Kong, and Zhao Lin
- Subjects
Proteasome Endopeptidase Complex ,Hypoxia-Inducible Factor 1 ,Histone Deacetylase 6 ,Hydroxamic Acids ,Histone Deacetylases ,Ubiquitin ,Tumor Cells, Cultured ,Humans ,HSP70 Heat-Shock Proteins ,Enzyme Inhibitors ,Molecular Biology ,biology ,Articles ,Cell Biology ,HDAC6 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Hsp90 ,Cell Hypoxia ,Protein Structure, Tertiary ,Hsp70 ,Cell biology ,Histone Deacetylase Inhibitors ,Biochemistry ,Hypoxia-inducible factors ,Von Hippel-Lindau Tumor Suppressor Protein ,biology.protein ,Histone deacetylase ,Tumor Suppressor Protein p53 ,Function (biology) - Abstract
Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1alpha expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1alpha expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1alpha levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1alpha by a mechanism that is independent of VHL and p53 and does not require the ubiquitin system. This degradation pathway involves the enhanced interaction of HIF-1alpha with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6.
- Published
- 2006
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