Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 (Retracted article. See vol. 18, 2024)
Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 (Retracted article. See vol. 18, 2024)
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通过转录抑制 MKK7 抑制 HDAC4 可减轻蛛网膜下腔出血后 JNK/c-Jun 依赖性神经元凋亡和早期脑损伤
DOI：
10.3389/fncel.2019.00468
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发表时间：
2019-10-25
影响因子：
5.3
通讯作者：
Yuan, Zhongmin
中科院分区：
文献类型：
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作者：
Wu, Liqiang;Zeng, Shulian;Yuan, Zhongmin
C-Jun氨基末端激酶(JNK)/c-Jun级联依赖的神经元凋亡已被认为是蛛网膜下腔出血(SAH)后早期脑损伤(EBI)的核心因素，但这一过程的分子机制迄今仍不完全清楚。在本研究中，我们发现TSA、SAHA、VPA和M344对泛组蛋白脱乙酰酶(HDAC)的抑制导致JNK和c-Jun的磷酸化显著降低，同时明显减少了缺钾引起的小脑颗粒神经元(CGN)的凋亡。进一步的研究表明，这些效应是由于HDAC抑制导致了对MKK7的转录抑制，MKK7是JNK的一个众所周知的上游激酶。使用小干扰RNA(SiRNAs)沉默各自的HDAC成员，筛选出MKK7转录和JNK/c-Jun激活所需的HDAC4。HDAC4特异性抑制剂LMK235呈剂量依赖性抑制MKK7转录和JNK/c-Jun活性。在功能上，通过敲除或LMK235抑制HDAC4可显著挽救缺钾诱导的CGN细胞凋亡。此外，给予LMK235显著改善SAH大鼠的EBI过程，与MKK7转录、JNK/c-Jun活性和神经细胞凋亡明显减少有关。总之，这些发现为研究HDAC4在选择性调控MKK7转录和JNK/c-Jun活性中的神经元凋亡的分子机制提供了新的见解。HDAC4抑制可能是预防MKK7/JNK/c-jun轴介导的神经疾病，包括SAH引起的EBI的潜在替代方案。
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 mechanisms 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 small interference RNAs (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.