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HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

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Cell Stress and Chaperones Aims and scope

Abstract

Histone deacetylase 6 (HDAC6) plays an important role in stress responses such as misfolded protein-induced aggresomes, autophagy, and stress granules. However, precisely how HDAC6 manages response during and after cellular stress remains largely unknown. This study aimed to investigate the effect of HDAC6 on various stress and post-stress recovery responses. We showed that HIF-1α protein levels were reduced in HDAC6 knockout (KO) MEFs compared to wild-type (WT) MEFs in hypoxia. Furthermore, under hypoxia, HIF-1α levels were also reduced following rescue with either a catalytically inactive or a ubiqiutin-binding mutant HDAC6. HDAC6 deacetylated and upregulated the stability of HIF-1α, leading to activation of HIF-1α function under hypoxia. Notably, both the deacetylase and ubiquitin-binding activities of HDAC6 contributed to HIF-1α stabilization, but only deacetylase activity was required for HIF-1α transcriptional activity. Suppression of HDAC6 enhanced the interaction between HIF-1α and HSP70 under hypoxic conditions. In addition to hypoxia, depletion of HDAC6 caused hypersensitivity to cell death during oxidative stress and post-stress recovery. However, HDAC6 depletion had no effect on cell death in response to heat shock or ionizing radiation. Overall, our data suggest that HDAC6 may serve as a critical stress regulator in response to different cellular stresses.

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Abbreviations

HDAC:

Histone deacetylase

HDACi:

HDAC inhibitor

HIF-1:

Hypoxia-inducible factor 1

H2O2 :

Hydrogen peroxide

HRE:

Hypoxic response element

HSP:

Heat shock protein

KO:

Knockout

MEF:

Mouse embryonic fibroblast

ODD:

Oxygen-dependent degradation

PTM:

Posttranslational modification

SG:

Stress granule

VHL:

von Hippel-Lindau

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Acknowledgements

We wish to thank Dr. Patrick Matthias (Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland) for providing HDAC6 KO and mutant MEFs and an anti-mHDAC6 antibody. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2014R1A1A2054026).

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Authors and Affiliations

  1. College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea

    Hyun-Wook Ryu, Hye-Rim Won, Dong Hoon Lee & So Hee Kwon

  2. Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, 03722, Republic of Korea

    Dong Hoon Lee

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  1. Hyun-Wook Ryu
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  2. Hye-Rim Won
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  3. Dong Hoon Lee
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Correspondence to So Hee Kwon.

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Ryu, HW., Won, HR., Lee, D.H. et al. HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery. Cell Stress and Chaperones 22, 253–261 (2017). https://doi.org/10.1007/s12192-017-0763-3

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  • DOI: https://doi.org/10.1007/s12192-017-0763-3

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