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Chaperone co-inducer BGP-15 inhibits histone deacetylases and enhances the heat shock response through increased chromatin accessibility.
Budzynski, Marek A; Crul, Tim; Himanen, Samu V; Toth, Noemi; Otvos, Ferenc; Sistonen, Lea; Vigh, Laszlo.
Afiliación
  • Budzynski MA; Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, FI-20520, Turku, Finland.
  • Crul T; Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, FI-20520, Turku, Finland.
  • Himanen SV; Biological Research Centre of the Hungarian Academy of Sciences, Szeged, 6726, Hungary.
  • Toth N; Faculty of Science and Engineering, Cell Biology, Åbo Akademi University, FI-20520, Turku, Finland.
  • Otvos F; Turku Centre for Biotechnology, Åbo Akademi University and University of Turku, FI-20520, Turku, Finland.
  • Sistonen L; Biological Research Centre of the Hungarian Academy of Sciences, Szeged, 6726, Hungary.
  • Vigh L; Biological Research Centre of the Hungarian Academy of Sciences, Szeged, 6726, Hungary.
Cell Stress Chaperones ; 22(5): 717-728, 2017 Sep.
Article en En | MEDLINE | ID: mdl-28474205
ABSTRACT
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 (HSPA1A/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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oximas / Piperidinas / Cromatina / Respuesta al Choque Térmico / Inhibidores de Histona Desacetilasas / Histona Desacetilasas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Stress Chaperones Año: 2017 Tipo del documento: Article País de afiliación: Finlandia

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oximas / Piperidinas / Cromatina / Respuesta al Choque Térmico / Inhibidores de Histona Desacetilasas / Histona Desacetilasas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Stress Chaperones Año: 2017 Tipo del documento: Article País de afiliación: Finlandia