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.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM.
To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined.
The expression of 95 genes was found to be upregulated by TSA, using paired supervised analysis with Significance Analysis of Microarrays software. Thirty-seven of these 95 genes had prognostic value for overall survival in a cohort of 206 newly diagnosed MM patients and their prognostic information was summed up in a histone acetylation score (HA Score); patients with the highest HA Score had the shorter overall survival. It is worth noting that MM cell lines or patients' primary MM cells with a high HA Score had a significant higher sensitivity to TSA, valproic acid, panobinostat or vorinostat.
In conclusion, the HA Score allows identification of MM patients with poor survival, who could benefit from HDACi treatment.
British Journal of Cancer 07/2013; 109(3). DOI:10.1038/bjc.2013.392 · 4.84 Impact Factor
[Show abstract][Hide abstract] 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.
The FASEB Journal 03/2012; 26(6):2437-45. DOI:10.1096/fj.11-193706 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The histone deacetylase (HDACs) family contains a family of enzymes, which are involved in modulating a wide range of cellular processes, such as proliferation, differentiation, apoptosis, and cell cycle progression. However, the biological function of HDAC5 in colorectal cancer has not been well established. In the current research, our data showed that the mRNA and protein levels of HDAC5 were up-regulated in human colorectal cancer cell lines. CCK-8 assay showed that overexpression of HDAC5 significantly promoted the proliferation of colorectal cancer cell lines including SW480 and HCT116. On the contrary, HDAC5 knockdown using small interfering RNA suppressed cell growth in colorectal tumor cells. At the molecular level, we demonstrated that HDAC5 promoted the expression of DLL4. In addition, down-regulation of DLL4 diminished the proliferative effects of HDAC5 in human colorectal cancer cells. Taken together, these results suggest that HDAC5 elevates the proliferation of colorectal cancer cells through up-regulation of DLL4. The current study might provide novel potential therapeutic targets in the treatment of colorectal cancer.
International Journal of Clinical and Experimental Medicine 07/2015; 8(4):6510-6. · 1.28 Impact Factor
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