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Molecular and Cellular Biology, March 2006, p. 2019-2028, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2019-2028.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Histone Deacetylase Inhibitors Induce VHL and Ubiquitin-Independent Proteasomal Degradation of Hypoxia-Inducible Factor 1{alpha}

Xianguo Kong, Zhao Lin, Dongming Liang, Donna Fath, Nianli Sang,* and Jaime Caro*

Cardeza Foundation for Hematologic Research and Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Received 3 September 2005/ Returned for modification 1 November 2005/ Accepted 4 January 2006

Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) 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-1{alpha} expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1{alpha} expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1{alpha} levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1{alpha} 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-1{alpha} with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6.

* Corresponding author. Mailing address for Jaime Caro: 1015 Walnut St., Room 807, Philadelphia, PA 19107. Phone: (215) 955-7775. Fax: (215) 923-3836. E-mail: jaime.caro{at}jefferson.edu. Mailing address for Nianli Sang: 1015 Walnut St., Room 711, Philadelphia, PA 19107. Phone: (215) 955-5118. Fax: (215) 955-2366. E-mail: Nianli.sang{at}jefferson.edu.

Molecular and Cellular Biology, March 2006, p. 2019-2028, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2019-2028.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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