title: Involvement of transcription factor XBP1s in the resistance of HDAC6 inhibitor Tubastatin A to superoxidation via acetylation-mediated proteasomal degradation.
abstract: HDAC6 is a major cytoplasmic deacetylase. XBP1s is a basic-region leucine zipper (bZIP) transcriptional factor. Despite their mutual involvement in the anti-oxidative process, there are no reports about their inter-protein interactions so far. Here we identified a direct link between HDAC6 inhibition and XBP1s transcription activity in anti-oxidative damage. We showed that the specific HDAC6 inhibitor Tubastatin A could up-regulate XBP1s transcriptional activity, thereby increasing anti-oxidative genes expression. Moreover, knock down of XBP1s could significantly abolish the cell growth protection afforded by Tubastatin A. We hypothesize that Tubastatin A acts to increase XBP1s protein levels that are dependent on its HDAC6 deacetylase inhibition via a mechanism involving acetylation-mediated proteasomal degradation, providing novel mechanistic insight into the anti-oxidative effects of HDAC6 inhibition.
authors.affiliation: School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Chang-mei
authors.initials: CM
authors.lastname: Liu
authors.affiliation: School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Xian-cao
authors.initials: XC
authors.lastname: Cao
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zang
authors.affiliation: National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: ybzhou@mail.shcnc.ac.cn.
authors.forename: Yu-bo
authors.initials: YB
authors.lastname: Zhou
authors.affiliation: School of Life Sciences, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004351:Drug Resistance / Q000502:physiology; D057809:HEK293 Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605545:Xbp1 protein, rat; C553587:tubastatin A; D046988:Proteasome Endopeptidase Complex; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6; Oxidative stress; Transcription regulation; Tubastatin A; XBP1s