The histone deacetylase inhibitor vorinostat prevents TNFα-induced necroptosis by regulating multiple signaling pathways.
Wang D1, Zhao M1, Chen G1, Cheng X1, Han X2, Lin S1, Zhang X1, Yu X3.
Author information
1Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China.2Department of Biochemistry, China Medical University, Shenyang, China.3Department of Stress Medicine, Beijing Institute of Basic Medical Sciences, Cognitive and Mental Health Research Center, #27 Taiping Road, Beijing, 100850, China. yuxd@bmi.ac.cn.
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.