Journal
CELL CYCLE
Volume 14, Issue 15, Pages 2520-2536Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1055426
Keywords
AMPK; deacetylation; HDAC5; HIF-1; Hsp70; nuclear export
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Funding
- NCI, National Institutes of Health (NIH) [R01-CA129494]
- PhD dissertation fellowship from Drexel University
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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-1 alpha accumulation and HIF-1 transactivation, whereas HDAC5 overexpression enhances HIF-1 stabilization and nuclear translocation. Mechanistically, we show that Hsp70 is a cytosolic substrate of HDAC5; and hyperacetylation renders Hsp70 higher affinity for HIF-1 binding, which correlates with accelerated degradation and attenuated nuclear accumulation of HIF-1 alpha. Physiologically, AMPK-triggered cytosolic shuttling of HDAC5 is critical; inhibition of either AMPK or HDAC5 impairs HIF-1 alpha 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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