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The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways

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Abstract

Histone deacetylase (HDAC) inhibitors are novel anticancer reagents that have recently been reported to have anti-inflammatory and neuroprotective effects; however, the mechanisms underlying their activities are largely undefined. The data from this study show that the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can protect L929 cells from TNFα-induced necroptosis. This effect involves multiple mechanisms, including the upregulation of cFLIPL expression, the enhanced activation of NFκB and p38 MAPK, and the inactivation of JNK. In addition, SAHA could initiate cell autophagy by inhibiting Akt and mTOR, which also play important roles in protecting cells from necroptosis. Because cell necroptosis is important for inflammation-related deterioration and neurodegenerative disease, our results indicate that preventing cell necrosis may be an important mechanism through which HDAC inhibitor compounds exert their anti-inflammatory or neuroprotective effects.

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Acknowledgments

We are grateful to Drs. Yan Li and Lingling Zhu for kindly providing the L929 and SH-SY5Y cell lines. This work was supported in part by Grant 2012CB518200 from the ‘‘973′’ Program of the Ministry of Science and Technology of China (to X. Yu) and by Grants 81000981 (to X. Zhang) and 31201041 (to G. Chen) from the National Natural Science Foundation of China.

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China

    Di Wang, Ming Zhao, Guozhu Chen, Xiang Cheng, Song Lin, Xuhui Zhang & Xiaodan Yu

  2. Department of Biochemistry, China Medical University, Shenyang, China

    Xiaoxi Han

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  1. Di Wang
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  2. Ming Zhao
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Correspondence to Xiaodan Yu.

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Wang, D., Zhao, M., Chen, G. et al. The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways. Apoptosis 18, 1348–1362 (2013). https://doi.org/10.1007/s10495-013-0866-y

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