Involvement of transcription factor XBP1s in the resistance of HDAC6 inhibitor Tubastatin A to superoxidation via acetylation-mediated proteasomal degradation

Yue Zhang; Chang-mei Liu; Xian-cao Cao; Yi Zang; Yu-bo Zhou; Jia Li

doi:10.1016/j.bbrc.2014.05.134

Involvement of transcription factor XBP1s in the resistance of HDAC6 inhibitor Tubastatin A to superoxidation via acetylation-mediated proteasomal degradation

Biochem Biophys Res Commun. 2014 Jul 18;450(1):433-9. doi: 10.1016/j.bbrc.2014.05.134. Epub 2014 Jun 6.

Authors

Yue Zhang¹, Chang-mei Liu¹, Xian-cao Cao¹, Yi Zang², Yu-bo Zhou³, Jia Li⁴

Affiliations

¹ 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.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ 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: [email protected].
⁴ 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: [email protected].

PMID: 24909686
DOI: 10.1016/j.bbrc.2014.05.134

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.

Keywords: HDAC6; Oxidative stress; Transcription regulation; Tubastatin A; XBP1s.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Animals
DNA-Binding Proteins / metabolism*
Drug Resistance / physiology
HEK293 Cells
Histone Deacetylase 6
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / drug effects*
Humans
Hydroxamic Acids / pharmacology*
Indoles / pharmacology*
PC12 Cells
Proteasome Endopeptidase Complex / metabolism*
Rats
Regulatory Factor X Transcription Factors
Transcription Factors / metabolism*
Transcriptional Activation / drug effects
Transcriptional Activation / physiology*
X-Box Binding Protein 1

Substances

DNA-Binding Proteins
Histone Deacetylase Inhibitors
Hydroxamic Acids
Indoles
Regulatory Factor X Transcription Factors
Transcription Factors
X-Box Binding Protein 1
XBP1 protein, human
Xbp1 protein, rat
tubastatin A
Proteasome Endopeptidase Complex
HDAC6 protein, human
Histone Deacetylase 6
Histone Deacetylases