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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Cell. Neurosci. | doi: 10.3389/fncel.2019.00468

Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7

 Zhongmin Yuan1*, Yezhong Wang1, Liqiang Wu1, Kunhua Hu2, Yali Cao1, Sisi Liu1, Ziyan Huang1, Shulian Zeng1, Huaidong Peng3, Cheng Zhi4, Miaoling Lai4 and Shanshan Ma2
  • 1Department of Neurosurgery, Second Affiliated Hospital of Guangzhou Medical University, China
  • 2Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, China
  • 3Department of Pharmacy, Second Affiliated Hospital of Guangzhou Medical University, China
  • 4Department of Pathology, Second Affiliated Hospital of Guangzhou Medical University, China

The c-Jun N-terminal kinase (JNK)/c-Jun cascade-dependent neuronal apoptosis has been identified as a central element for early brain injury (EBI) following subarachnoid hemorrhage (SAH), but the molecular mechanism underlying this process are still thoroughly undefined to date. In this study, we found that pan-histone deacetylase (HDAC) inhibition by TSA, SAHA, VPA and M344 led to a remarkable decrease in the phosphorylation of JNK and c-Jun, concomitant with a significant abrogation of apoptosis caused by potassium deprivation in cultured cerebellar granule neurons (CGNs). Further investigation showed that these effects resulted from HDAC inhibition-induced transcriptional suppression of MKK7, a well-known upstream kinase of JNK. Using siRNAs to silence the respective HDAC members, HDAC4 was screened to be required for MKK7 transcription and JNK/c-Jun activation. LMK235, a specific HDAC4 inhibitor, dose-dependently suppressed MKK7 transcription and JNK/c-Jun activity. Functionally, HDAC4 inhibition via knockdown or LMK235 significantly rescued CGN apoptosis induced by potassium deprivation. Moreover, administration of LMK235 remarkably ameliorated the EBI process in SAH rats, associated with an obvious reduction in MKK7 transcription, JNK/c-Jun activity, and neuronal apoptosis. Collectively, the findings provide new insights into the molecular mechanism of neuronal apoptosis regarding HDAC4 in the selective regulation of MKK7 transcription and JNK/c-Jun activity. HDAC4 inhibition could be a potential alternative to prevent MKK7/JNK/c-Jun axis-mediated nervous disorders, including SAH-caused EBI.

Keywords: MKK7, HDAC4, Neuronal apoptosis, Subarachnoid hemorrhage (SAH), Early brain injury (EBI), JNK/c-JUN

Received: 18 Jan 2019; Accepted: 01 Oct 2019.

Copyright: © 2019 Yuan, Wang, Wu, Hu, Cao, Liu, Huang, Zeng, Peng, Zhi, Lai and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Zhongmin Yuan, Department of Neurosurgery, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong Province, China, yzm@gzhmu.edu.cn