title: AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol.
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.
authors.affiliation: a Department of Biology and Graduate Program of Biological Sciences; CoAS; Department of Pathology & Laboratory Medicine; DUCOM; Drexel University ; Philadelphia , PA USA.
authors.forename: Shuyang
authors.initials: S
authors.lastname: Chen
authors.forename: Chengqian
authors.initials: C
authors.lastname: Yin
authors.forename: Taotao
authors.initials: T
authors.lastname: Lao
authors.forename: Dongming
authors.initials: D
authors.lastname: Liang
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Nianli
authors.initials: N
authors.lastname: Sang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D061986:MCF-7 Cells; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: C497442:HIF1A protein, human; D018840:HSP70 Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D055372:AMP-Activated Protein Kinases; C404500:HDAC5 protein, human; D006655:Histone Deacetylases
keywords: AMPK; HDAC5; HIF-1; Hsp70; deacetylation; nuclear export