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Inhibitors of Histone Deacetylases Enhance Neurotoxicity of DNA Damage

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Abstract

The nonselective inhibitors of class I/II histone deacetylases (HDACs) including trichostatin A and the clinically used suberoylanilide hydroxamic acid (SAHA, vorinostat) are neuroprotective in several models of neuronal injury. Here, we report that in cultured cortical neurons from newborn rats and in the cerebral cortex of whole neonate rats, these HDAC inhibitors exacerbated cytotoxicity of the DNA double-strand break (DSB)-inducing anticancer drug etoposide by enhancing apoptosis. Similar neurotoxic interactions were also observed in neurons that were treated with other DNA damaging drugs including cisplatin and camptothecin. In addition, in rat neonates, SAHA increased cortical neuron apoptosis that was induced by a single injection of the NMDA receptor antagonist dizocilpine (MK801). In etoposide-treated neurons, the nonselective HDAC inhibition resulted in more DSBs. It also potentiated etoposide-induced accumulation and phosphorylation of the pro-apoptotic transcription factor p53. Moreover, nonselective HDAC inhibition exacerbated neuronal apoptosis that was induced by the overexpressed p53. Importantly, such effects cannot be fully explained by inhibition of HDAC1, which is known to play a role in DSB repair and regulation of p53. The specific HDAC1 inhibitor MS275 only moderately enhanced etoposide-induced neuronal death. Although in etoposide-treated neurons MS275 increased DSBs, it did not affect activation of p53. Our findings suggest that besides HDAC1, there are other class I/II HDACs that participate in neuronal DNA damage response attenuating neurotoxic consequences of genotoxic insults to the developing brain.

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Abbreviations

β-gal:

β-Galactosidase

BH3:

Bcl-2 homology domain-3

BME:

Basal medium Eagle

DIV:

Day in vitro

DSB:

Double-strand break

E2F1:

E2 promoter binding factor-1

HAT:

Histone acetyltransferase

HDACi:

HDAC inhibitor

HDAC:

Histone deacetylase

SAHA:

Suberoylanilide hydroxamic acid

SBHA:

Suberoyl bis-hydroxamic acid

SSB:

Single-strand break

TSA:

Trichostatin A

γH2Ax:

Histone H2Ax variant containing the phosphorylated serine-139 residue

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Acknowledgments

This work was supported by NIH (NS073584 and 8P30GM103507 to MH), NSF (IOS1021860 to MH), and the Commonwealth of Kentucky Challenge for Excellence Fund. The authors wish to thank Ms. Jing-Juan Zheng for excellent technical assistance and Mr. Justin Hallgren for critical reading of the manuscript.

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Authors do not have any conflict of interest concerning this manuscript.

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  1. Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, 511 S. Floyd St., MDR616, Louisville, KY, 40292, USA

    A. Vashishta & M. Hetman

  2. Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40292, USA

    M. Hetman

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  1. A. Vashishta
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Vashishta, A., Hetman, M. Inhibitors of Histone Deacetylases Enhance Neurotoxicity of DNA Damage. Neuromol Med 16, 727–741 (2014). https://doi.org/10.1007/s12017-014-8322-x

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