Chaperone co-inducer BGP-15 inhibits histone deacetylases and enhances the heat shock response through increased chromatin accessibility

• Published in: Cell stress & chaperones Vol. 22; no. 5; pp. 717 - 728
• Main Authors: Budzyński, Marek A., Crul, Tim, Himanen, Samu V., Toth, Noemi, Otvos, Ferenc, Sistonen, Lea, Vigh, Laszlo
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer 01-09-2017; Springer Netherlands; Springer Nature B.V
• Subjects: Accessibility; Activation; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carrier Proteins - metabolism; Cell Biology; Cell Line; Cell Survival - drug effects; Chromatin; Chromatin - metabolism; Chromatin Immunoprecipitation; Co-Repressor Proteins; Defects; Drug development; Heat shock factors; Heat shock proteins; Heat Shock Transcription Factors - genetics; Heat Shock Transcription Factors - metabolism; Heat stress; Heat tolerance; Heat treatment; Heat-Shock Response - drug effects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Homeostasis; HSF1 protein; HSP40 Heat-Shock Proteins - chemistry; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Immunology; Intracellular Signaling Peptides and Proteins - metabolism; Metabolic disorders; Mice; Mode of action; Molecular Chaperones; Neurodegenerative diseases; Neurological diseases; Neurosciences; Nuclear Proteins - metabolism; Original Paper; Oximes - pharmacology; Pharmacology; Piperidines - pharmacology; Protein Binding; Proteins; Receptor, Notch4 - metabolism; Trichostatin A; Valproic acid; Histone deacetylase (HDAC); TSA; Transcription; Stress response; VPA; Heat shock factor protein 1 (HSF1)
• ISSN: 1355-8145; 1466-1268
• DOI: 10.1007/s12192-017-0798-5

Defects in cellular protein homeostasis are associated with many severe and prevalent pathological conditions such as neurodegenerative diseases, muscle dystrophies, and metabolic disorders. One way to counteract these defects is to improve the protein homeostasis capacity through induction of the heat shock response. Despite numerous attempts to develop strategies for chemical activation of the heat shock response by heat shock transcription factor 1 (HSF1), the underlying mechanisms of drug candidates' mode of action are poorly understood. To lower the threshold for the heat shock response activation, we used the chaperone co-inducer BGP-15 that was previously shown to have beneficial effects on several proteinopathic disease models. We found that BGP-15 treatment combined with heat stress caused a substantial increase in HSF1-dependent heat shock protein 70 (HSPA1 A/B) expression already at a febrile range of temperatures. Moreover, BGP-15 alone inhibited the activity of histone deacetylases (HDACs), thereby increasing chromatin accessibility at multiple genomic loci including the stress-inducible HSPA1A. Intriguingly, treatment with well-known potent HDAC inhibitors trichostatin A and valproic acid enhanced the heat shock response and improved cytoprotection. These results present a new pharmacological strategy for restoring protein homeostasis by inhibiting HDACs, increasing chromatin accessibility, and lowering the threshold for heat shock response activation.