The emerging role of histone deacetylases (HDACs) in UPR regulation

Department of Experimental Therapeutics and Radiation Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Methods in enzymology (Impact Factor: 2.09). 01/2011; 490:159-74. DOI: 10.1016/B978-0-12-385114-7.00010-6
Source: PubMed


Although the function of histone deacetylases (HDACs) have primarily been associated with influencing transcription through chromatin remodeling, the capacity of these enzymes to interface with a diverse array of biologic processes by modulating a growing list of nonhistone substrates has gained recent attention. Recent investigations have demonstrated the potential of HDACs to directly regulate the unfolded protein response (UPR) through acetylation of its central regulatory protein, Grp78. Further, this appears to be an important mechanism underlying the anti-tumor activity of HDAC inhibitors. Herein, we provide a summary of the literature supporting the role HDACs play in regulating the UPR and a detailed description of methods to allow for the study of both acetylation of nonhistone proteins and UPR pathway activation following HDAC inhibition.

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    • "Histone deacetylase inhibitors induce apoptosis by dowregulation of Bcl-2 family members (Mitsiades et al, 2003; Khan et al, 2004) and overcome drug resistance mediated by the BM environment (Mitsiades et al, 2003). Furthermore, glucose-regulated protein 78 (GRP78) was recently identified as a novel non-histone target of HDACi (Rao et al, 2010; Kahali et al, 2011). Glucose-regulated protein 78 has a central role in the unfolded protein response (UPR). "
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    ABSTRACT: Post-translational modification through protein acetylation is emerging as an important mode of cellular regulation. We have previously demonstrated the role that glucose-regulated protein 78 kDa (GRP78) acetylation and subsequent activation of the unfolded protein response (UPR) play in the antitumor activity of class I histone deacetylase (HDAC) inhibitors, which primarily target class I HDACs. In this study, we explored the contributory role these class I HDACs may play in UPR regulation. Binding studies were performed using immunoprecipitation/immunoblotting following dual-transfection with HA-tagged GRP78 and FLAG-tagged HDACs. Subcellular localization was performed using Western blot of fractionated cell lysates and confocal microscopy. Individual HDACs were inhibited using RNA interference. We identified the potential of HDACs 1, 2, and 3 to bind to GRP78. These HDACs colocalized with GRP78 in the endoplasmic reticulum (ER). Inhibition of individual HDACs resulted in GRP78 acetylation and selective activation of the UPR. Although traditionally viewed as nuclear enzymes, we demonstrate that Class I HDACs localize to the ER, bind to GRP78, and selectively activate the UPR, representing a novel mode of UPR regulation and mechanism of action of HDAC inhibitors.
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