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

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 (HIF-1) 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 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 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 protein via a VHL-independent mechanism and reduction of HIF-1 transcriptional activity. HIF-1 inhibition by LAQ824 was associated with HIF-1 acetylation and polyubiquitination. HIF-1 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. Hydroxamic acid derivatives with known activity against both class I and class II HDACs were effective in inhibiting HIF-1 at low nanomolar concentrations. In contrast, valproic acid and trapoxin were able to inhibit HIF-1 only at concentrations that are effective against class II HDACs. Coimmunoprecipitation studies showed that class II HDAC4 and HDAC6 were associated with HIF-1 protein. Inhibition by small interfering RNA of HDAC4 and HDAC6 reduced HIF-1 protein expression and transcriptional activity. Taken together, these results suggest that class II HDACs are associated with HIF-1 stability and provide a rationale for targeting HIF-1 with HDAC inhibitors against class II isozymes. (Cancer Res 2006; 66(17): 8814-21)

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