AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol

摘要: 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 its role in homesostasis remain unclear. Here, we demonstrate that depends on a cytosolic, enzymatically active HDAC5. HDAC5 knockdown impairs hypoxia-induced HIF-1α accumulation transactivation, overexpression enhances stabilization nuclear translocation. Mechanistically, show Hsp70 is cytosolic substrate HDAC5; hyperacetylation renders higher affinity binding, which correlates with accelerated degradation attenuated HIF-1α. Physiologically, AMPK-triggered shuttling critical; inhibition either or under hypoxia low glucose conditions. Finally, specifically suppressing sufficient inhibit tumor cell proliferation hypoxic Our data delineate novel link between AMPK, sensor, HIF-1, major driver ATP production, indicating inhibiting may selectively suppress survival cells.