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HSP72 functionally inhibits the anti-neoplastic effects of HDAC inhibitors

Kazuyasu Fujii¹, Norihiro Suzuki², Nozomi Jimura¹

¹Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima, Japan.

Journal of Dermatological Science

|February 4, 2018

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.

Insights

Heat shock protein 72 (HSP72) overexpression inhibits cancer cell death induced by histone deacetylase inhibitors (HDACi). Understanding this mechanism is crucial for improving HDACi cancer therapy effectiveness.

Area of Science:

Oncology
Molecular Biology
Biochemistry

Background:

Histone deacetylase inhibitors (HDACi) show variable anticancer effects due to poorly understood molecular mechanisms.
Heat shock 70 kDa protein 1A (HSPA1A, or HSP72) is overexpressed in valproic acid (VPA)-resistant cancer cells.
Heat shock protein inhibition enhances HDACi cytotoxicity, but HSP72's role in resistance is unclear.

Purpose of the Study:

To elucidate the mechanisms by which HSP72 contributes to resistance against HDAC inhibitors.
To investigate the functional impact of HSP72 overexpression on HDAC inhibitor-induced apoptosis.

Main Methods:

Established a Jurkat cell line with stable overexpression of HSP72.
Assessed the effects of vorinostat and VPA on apoptosis in HSP72-overexpressing cells versus control cells.
Analyzed apoptosis markers, caspase activity, mitochondrial potential, and specific protein expression levels.

Main Results:

HSP72 overexpression significantly reduced HDACi-induced apoptosis, evidenced by decreased annexin V staining, sub-G1 fraction, and PARP cleavage.
Overexpression of HSP72 suppressed HDACi-mediated increases in caspase activity and decreases in mitochondrial membrane potential.
Basal levels of Bcl-2, p-Bad, and XIAP were elevated in HSP72-overexpressing cells, while Bid cleavage and Bad suppression by HDACi were diminished. Vorinostat-induced histone hyperacetylation was also reduced.

Conclusions:

HSP72 overexpression directly inhibits apoptosis induced by HDAC inhibitors.
HSP72 plays a critical role in conferring resistance to HDAC inhibitors, impacting key apoptotic pathways.

Read full analysis

Keywords:

Apoptosis HDAC inhibitor HSP72 Sensitivity

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