{"data":{"id":"10.6084/m9.figshare.1444403.v3","type":"dois","attributes":{"doi":"10.6084/m9.figshare.1444403.v3","prefix":"10.6084","suffix":"m9.figshare.1444403.v3","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Shuyang Chen","affiliation":[],"nameIdentifiers":[]},{"name":"Chengqian Yin","affiliation":[],"nameIdentifiers":[]},{"name":"Taotao Lao","affiliation":[],"nameIdentifiers":[]},{"name":"Dongming Liang","affiliation":[],"nameIdentifiers":[]},{"name":"He, Dan","nameType":"Personal","givenName":"Dan","familyName":"He","affiliation":[],"nameIdentifiers":[]},{"name":"Chenguang Wang","affiliation":[],"nameIdentifiers":[]},{"name":"Nianli Sang","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2015,"subjects":[{"subject":"Immunology"},{"subject":"FOS: Clinical medicine","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Clinical medicine","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Hematology"},{"subject":"Cancer"},{"subject":"Chemistry"},{"subject":"Physiology"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Biological sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Molecular Biology"},{"subject":"Genetics"},{"subject":"Cell Biology"},{"subject":"Biochemistry"}],"contributors":[],"dates":[{"date":"2015-10-08","dateType":"Created"},{"date":"2019-06-03","dateType":"Updated"},{"date":"2015","dateType":"Issued"}],"language":null,"types":{"ris":"DATA","bibtex":"misc","citeproc":"dataset","schemaOrg":"Dataset","resourceType":"Dataset","resourceTypeGeneral":"Dataset"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/15384101.2015.1055426","relatedIdentifierType":"DOI"},{"relationType":"IsPreviousVersionOf","relatedIdentifier":"10.6084/m9.figshare.1444403","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["1135962 Bytes"],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"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.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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