{"data":{"id":"10.6084/m9.figshare.1444403.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.1444403.v1","prefix":"10.6084","suffix":"m9.figshare.1444403.v1","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":"2015-08-03","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":"SummaryHypoxia-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 suppress 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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