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Cell Death Dis. 2017 Jan 26;8(1):e2570. doi: 10.1038/cddis.2016.465.

Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

Wu Y1,2, Ma S3,4, Xia Y1,2, Lu Y1,2, Xiao S1,2, Cao Y1,2, Zhuang S1,2, Tan X1,2, Fu Q5, Xie L1,2, Li Z6, Yuan Z1,2,3.

Author information

1
Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.
2
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
3
Guangdong Province Key laboratory of Brain Function and Disease, Guangzhou 510006, China.
4
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
5
Department of General Dentistry, 323 Hospital of the People's Liberation Army, Xi'an, China.
6
Department of Radiology, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.

Abstract

Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.

PMID:
28125090
PMCID:
PMC5386373
DOI:
10.1038/cddis.2016.465
[Indexed for MEDLINE]
Free PMC Article

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