HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors

Kazuyasu Fujii, Norihiro Suzuki, Nozomi Jimura, Masashi Idogawa, Tadashi Kondo, Keiji Iwatsuki, Takuro Kanekura

Research output: Contribution to journalArticle

Abstract

Background: The anticancer effects of histone deacetylase inhibitors (HDACi) vary between patients, and their molecular mechanisms remain poorly understood. Previously, we have identified heat shock 70 kDa protein 1A (HSPA1A, also known as HSP72) as the most overexpressed protein in valproic acid (VPA)-resistant cell lines. KNK437, an inhibitor of heat shock proteins, enhanced the cytotoxic effects of not only VPA but also vorinostat, another HDACi. However, the mechanisms underlying the role of HSP72 in resistance against HDACi remain largely unknown. Objective: The purpose of this study was to identify the mechanisms underlying the role of HSP72 in HDACi resistance. Methods: We established an HSP72-overexpressing Jurkat cell line and used it to assess the functional role of HSP72 following treatment with the HDACi vorinostat and VPA. Results: HDACi-induced apoptosis, assessed using annexin V assays, sub-G1 fraction analysis, and PARP cleavage, was significantly lower in HSP72-overexpressing cells than in control cells. The HDACi-induced upregulation in caspase-3, -8, and -9 activity, as well as the HDACi-induced reduction in mitochondrial membrane potential, were also suppressed following HSP72 overexpression. The basal expression levels of Bcl-2, phosphorylated Bad, and XIAP increased in HSP72-overexpressing cells, whereas HDACi-induced Bid truncation and the suppression of Bad expression. Furthermore, vorinostat-induced histone hyperacetylation was also diminished in HSP72-overexpressing cells. Conclusion: These findings clearly demonstrate that HSP72 inhibits HDACi-induced apoptosis.

Original languageEnglish
JournalJournal of Dermatological Science
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Histone Deacetylase Inhibitors
Valproic Acid
Cells
Apoptosis
Cell Line
HSP70 Heat-Shock Proteins
Jurkat Cells
Caspase 8
Mitochondrial Membrane Potential
Annexin A5
Heat-Shock Proteins
Caspase 3
Histones
Assays
Up-Regulation
Membranes

Keywords

  • Apoptosis
  • HDAC inhibitor
  • HSP72
  • Sensitivity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology

Cite this

Fujii, K., Suzuki, N., Jimura, N., Idogawa, M., Kondo, T., Iwatsuki, K., & Kanekura, T. (Accepted/In press). HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors. Journal of Dermatological Science. https://doi.org/10.1016/j.jdermsci.2018.01.002

HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors. / Fujii, Kazuyasu; Suzuki, Norihiro; Jimura, Nozomi; Idogawa, Masashi; Kondo, Tadashi; Iwatsuki, Keiji; Kanekura, Takuro.

In: Journal of Dermatological Science, 01.01.2018.

Research output: Contribution to journalArticle

Fujii, Kazuyasu ; Suzuki, Norihiro ; Jimura, Nozomi ; Idogawa, Masashi ; Kondo, Tadashi ; Iwatsuki, Keiji ; Kanekura, Takuro. / HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors. In: Journal of Dermatological Science. 2018.
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