Journal article
AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol
Cell cycle (Georgetown, Tex.), Vol.14(15), pp.2520-2536
03 Aug 2015
PMCID: PMC4614078
PMID: 26061431
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Hypoxia-inducible factor 1 (HIF-1) transcriptionally promotes production of adenosine triphosphate (ATP) whereas AMPK senses and regulates cellular energy homeostasis. A histone deacetylase (HDAC) activity has been proven to be critical for HIF-1 activation but the underlying mechanism and its role in energy homesostasis remain unclear. Here, we demonstrate that HIF-1 activation depends on a cytosolic, enzymatically active HDAC5. HDAC5 knockdown impairs hypoxia-induced HIF-1α accumulation and HIF-1 transactivation, whereas HDAC5 overexpression enhances HIF-1α stabilization and nuclear translocation. Mechanistically, we show that Hsp70 is a cytosolic substrate of HDAC5; and hyperacetylation renders Hsp70 higher affinity for HIF-1α binding, which correlates with accelerated degradation and attenuated nuclear accumulation of HIF-1α. Physiologically, AMPK-triggered cytosolic shuttling of HDAC5 is critical; inhibition of either AMPK or HDAC5 impairs HIF-1α nuclear accumulation under hypoxia or low glucose conditions. Finally, we show specifically suppressing HDAC5 is sufficient to inhibit tumor cell proliferation under hypoxic conditions. Our data delineate a novel link between AMPK, the energy sensor, and HIF-1, the major driver of ATP production, indicating that specifically inhibiting HDAC5 may selectively suppress the survival and proliferation of hypoxic tumor cells.
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Details
- Title
- AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol
- Creators
- Shuyang Chen - Drexel UniversityChengqian Yin - Drexel UniversityTaotao Lao - Drexel UniversityDongming Liang - Drexel UniversityDan He - Drexel UniversityChenguang Wang - Institute of Radiation Medicine; The Chinese Academy of Medical Sciences; Tianjin, China; Department of Radiation Protection; Peking Union Medical College; Beijing, ChinaNianli Sang - Thomas Jefferson University
- Publication Details
- Cell cycle (Georgetown, Tex.), Vol.14(15), pp.2520-2536
- Publisher
- Taylor & Francis
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Identifiers
- 991019168107704721
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- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology