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[Cancer Research 66, 8814-8821, September 1, 2006]
© 2006 American Association for Cancer Research


Experimental Therapeutics, Molecular Targets, and Chemical Biology

Class II Histone Deacetylases Are Associated with VHL-Independent Regulation of Hypoxia-Inducible Factor 1{alpha}

David Z. Qian1, Sushant K. Kachhap1, Spencer J. Collis1, Henk M.W. Verheul1, Michael A. Carducci1, Peter Atadja2 and Roberto Pili1

1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins School of Medicine, Baltimore, Maryland and 2 Novartis Research Institute, Cambridge, Massachusetts

Requests for reprints: Roberto Pili, Baunting-Blaustein Cancer Research, Building 1M52, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-502-7482; Fax: 410-614-8160; E-mail: rpili{at}jhmi.edu.

Hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) plays a critical role in transcriptional gene activation involved in tumor angiogenesis. A novel class of agents, the histone deacetylase (HDAC) inhibitors, has been shown to inhibit tumor angiogenesis and HIF-1{alpha} protein expression. However, the molecular mechanism responsible for this inhibition remains to be elucidated. In the current study, we investigated the molecular link between HIF-1{alpha} inhibition and HDAC inhibition. Treatment of the VHL-deficient human renal cell carcinoma cell line UMRC2 with the hydroxamic HDAC inhibitor LAQ824 resulted in a dose-dependent inhibition of HIF-1{alpha} protein via a VHL-independent mechanism and reduction of HIF-1{alpha} transcriptional activity. HIF-1{alpha} inhibition by LAQ824 was associated with HIF-1{alpha} acetylation and polyubiquitination. HIF-1{alpha} immunoprecipitates contained HDAC activity. Then, we tested different classes of HDAC inhibitors with diverse inhibitory activity of class I versus class II HDACs and assessed their capability of targeting HIF-1{alpha}. Hydroxamic acid derivatives with known activity against both class I and class II HDACs were effective in inhibiting HIF-1{alpha} at low nanomolar concentrations. In contrast, valproic acid and trapoxin were able to inhibit HIF-1{alpha} only at concentrations that are effective against class II HDACs. Coimmunoprecipitation studies showed that class II HDAC4 and HDAC6 were associated with HIF-1{alpha} protein. Inhibition by small interfering RNA of HDAC4 and HDAC6 reduced HIF-1{alpha} protein expression and transcriptional activity. Taken together, these results suggest that class II HDACs are associated with HIF-1{alpha} stability and provide a rationale for targeting HIF-1{alpha} with HDAC inhibitors against class II isozymes. (Cancer Res 2006; 66(17): 8814-21)




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Copyright © 2006 by the American Association for Cancer Research.