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Abstract LB-124: Histone deacetylase 5 stabilizes HIF-1α through Hsp70 deacetylation in cytosol
Journal article   Peer reviewed

Abstract LB-124: Histone deacetylase 5 stabilizes HIF-1α through Hsp70 deacetylation in cytosol

Shuyang Chen, Chengqian Yin, Taotao Lao, Dongming Liang and Nianli Sang
Cancer research (Chicago, Ill.), v 74(19_Supplement), pp LB-124-LB-124
01 Oct 2014
DOI: https://doi.org/10.1158/1538-7445.AM2014-LB-124

Abstract

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-1 function has been considered a therapeutic target for multiple diseases. Histone deacetylase (HDAC) activity has been involved in regulating HIF function and some HDAC inhibitors (HDACIs) have been documented to repress HIF-1 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 required for HIF-1 function. We present data here to show that histone deacetylase 5 (HDAC5) is required for HIF-1α protein stability. Knockdown of HDAC5 impaired hypoxic accumulation of HIF-1α and HIF-1 function. Furthermore, overexpression of HDAC5 enhanced HIF-1α stability and nuclear accumulation. Specifically, HDAC5 mutant exclusively localized at cytosol is sufficient for this function, stabilizing HIF-1α more efficiently than wild-type HDAC5. We further demonstrate that heat shock 70 kD protein (Hsp70) is a cytosolic substrate of HDAC5; and acetylation of Hsp70 promotes its association with HIF-1α and HIF-1α degradation. Taken together, our data suggest that deacetylation of Hsp70 catalyzed by HDAC5 facilitates the stabilization and hypoxic accumulation of HIF-1α. These findings also suggest that HDAC5 could be a potential target for therapies based on modulating HIF-1 function. Citation Format: Shuyang Chen, Chengqian Yin, Taotao Lao, Dongming Liang, Nianli Sang. Histone deacetylase 5 stabilizes HIF-1α through Hsp70 deacetylation in cytosol. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-124. doi:10.1158/1538-7445.AM2014-LB-124

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