Abstract 4733: Function of cytoplasmic histone deacetylase 5 is required for HIF-1α stability

Abstract Hypoxia is frequently associated with solid tumors and ischemic disorders, which are the top two leading causes of mortality in the world. Hypoxia-inducible factor 1 is a major regulator of angiogenesis and cellular adaptation to hypoxia. Accordingly HIF function has been considered a therapeutic target for multiple diseases. Histone deacetylase (HDAC) activity has been involved in regulating HIF function and HDAC inhibitors (HDACIs) have been documented to repress HIF function. However, histone deacetylases encompass multiple members, each has different cellular functions. HDACIs in clinical application or under development generally inhibit more than one HDAC. It is unclear which specific member of the HDAC family is involved in the regulation of HIF function. We present data here to show that histone deacetylase 5 (HDAC5) is required for HIF-1α protein stability. Knock-down of HDAC5 impaired hypoxic accumulation of HIF-1α and its function. In contrast, knock-down of HDAC1, HDAC3 or HDAC6 showed little or no effect. On the other hand, overexpression of HDAC5 enhanced HIF-1α stability. Specifically, cytosol localized HDAC5 mutant shows stronger effects on stabilizing HIF-1α compared to wild-type HDAC5. Mutation demolishing the deacetylase activity abolished the ability of HDAC5 to stabilize HIF-1α. Taken together, our data suggest that a cytosolic deacetylase activity of HDAC5 is required to stabilize HIF-1α. These findings also suggest that HDAC5 could be biological target for therapies based on modulating HIF function. This work is supported in part by grant R01-CA129494 (N.S.) from NCI, NIH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4733. doi:1538-7445.AM2012-4733