Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7
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 f...
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| Format: | Article |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2019.00468/full |
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| author | Liqiang Wu Liqiang Wu Shulian Zeng Shulian Zeng Yali Cao Yali Cao Ziyan Huang Ziyan Huang Sisi Liu Sisi Liu Huaidong Peng Cheng Zhi Shanshan Ma Shanshan Ma Kunhua Hu Kunhua Hu Zhongmin Yuan Zhongmin Yuan Zhongmin Yuan |
| author_facet | Liqiang Wu Liqiang Wu Shulian Zeng Shulian Zeng Yali Cao Yali Cao Ziyan Huang Ziyan Huang Sisi Liu Sisi Liu Huaidong Peng Cheng Zhi Shanshan Ma Shanshan Ma Kunhua Hu Kunhua Hu Zhongmin Yuan Zhongmin Yuan Zhongmin Yuan |
| author_sort | Liqiang Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T07:48:06Z |
| format | Article |
| id | doaj.art-9ff675927305440f8a997d2f59ccd641 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-04-14T07:48:06Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-9ff675927305440f8a997d2f59ccd6412022-12-22T02:05:17ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022019-10-011310.3389/fncel.2019.00468449043Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7Liqiang Wu0Liqiang Wu1Shulian Zeng2Shulian Zeng3Yali Cao4Yali Cao5Ziyan Huang6Ziyan Huang7Sisi Liu8Sisi Liu9Huaidong Peng10Cheng Zhi11Shanshan Ma12Shanshan Ma13Kunhua Hu14Kunhua Hu15Zhongmin Yuan16Zhongmin Yuan17Zhongmin Yuan18Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaKey Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaKey Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaKey Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaKey Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaKey Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, ChinaDepartment of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Pathology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, ChinaDepartment of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaGuangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, ChinaDepartment of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaKey Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Ministry of Education of China, Institute of Neuroscience of Guangzhou Medical University, Guangzhou, ChinaGuangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, ChinaThe 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.https://www.frontiersin.org/article/10.3389/fncel.2019.00468/fullMKK7JNKc-JunHDAC4neuronal apoptosissubarachnoid hemorrhage |
| spellingShingle | Liqiang Wu Liqiang Wu Shulian Zeng Shulian Zeng Yali Cao Yali Cao Ziyan Huang Ziyan Huang Sisi Liu Sisi Liu Huaidong Peng Cheng Zhi Shanshan Ma Shanshan Ma Kunhua Hu Kunhua Hu Zhongmin Yuan Zhongmin Yuan Zhongmin Yuan Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 Frontiers in Cellular Neuroscience MKK7 JNK c-Jun HDAC4 neuronal apoptosis subarachnoid hemorrhage |
| title | Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 |
| title_full | Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 |
| title_fullStr | Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 |
| title_full_unstemmed | Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 |
| title_short | Inhibition of HDAC4 Attenuated JNK/c-Jun-Dependent Neuronal Apoptosis and Early Brain Injury Following Subarachnoid Hemorrhage by Transcriptionally Suppressing MKK7 |
| title_sort | inhibition of hdac4 attenuated jnk c jun dependent neuronal apoptosis and early brain injury following subarachnoid hemorrhage by transcriptionally suppressing mkk7 |
| topic | MKK7 JNK c-Jun HDAC4 neuronal apoptosis subarachnoid hemorrhage |
| url | https://www.frontiersin.org/article/10.3389/fncel.2019.00468/full |
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