Neuroprotection by Histone Deacetylase-7 (HDAC7) Occurs by Inhibition of c-jun Expression through a Deacetylase-independent Mechanism

Abstract

Histone deacetylase (HDAC) 7 is a member of the HDAC family of deacetylases. Although some of the HDAC proteins have been shown to regulate neuronal survival and death, whether HDAC7 has a similar role is not known. In this study, we show that HDAC7 protects neurons from apoptosis. In cerebellar granule neurons (CGNs) primed to undergo apoptosis by low potassium treatment, expression of HDAC7 protein is reduced. Reduced expression is also observed in CGNs induced to die by pharmacological inhibition of the proteasome, in cortical neurons treated with homocysteic acid, and in the striatum of R6/2 transgenic mice, a commonly used genetic model of Huntington disease. Forced expression of HDAC7 in cultured CGNs blocks low potassium-induced death, and shRNA-mediated suppression of its expression induces death in otherwise healthy neurons. HDAC7-mediated neuroprotection does not require its catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Moreover, pharmacological inhibitors of the PI3K-Akt or Raf-MEK-ERK signaling pathways or that of PKA, PKC, and Ca 2؉ /calmodulin-dependent protein kinase fail to reduce neuroprotection by HDAC7. We show that stimulation of c-jun expression, an essential feature of neuronal death, is prevented by HDAC7. shRNA-mediated suppression of HDAC7 expression leads to an increase in c-jun expression. Inhibition of c-jun expression by HDAC7 is mediated at the transcriptional level by its direct association with the c-jun gene promoter. Taken together, our results indicate that HDAC7 is a neuroprotective protein acting by a mechanism that is independent of its deacetylase activity but involving the inhibition of c-jun expression.Histone deacetylases (HDACs) 2 are the catalytic subunits of multiprotein complexes that deacetylate specific lysines in the tail residues of histones, resulting in the compaction of chromatin into a transcriptionally repressed state (reviewed in Refs. 1, 2). Although best studied for their effects on histones and transcriptional activity, it is now known that HDACs regulate the acetylation status of a number of other non-histone proteins, suggesting complex functions of HDACs (1, 2). The 18 HDACs expressed in mammals have been grouped into four classes. Class I HDACs (HDAC1-3 and HDAC8) are composed primarily of a catalytic domain, expressed ubiquitously, and localize to the nucleus where they serve as transcriptional repressors. Class II HDACs (HDAC4 -7, HDAC9, and HDAC10) are larger proteins with an N-terminal regulatory domain involved in protein-protein interactions. These HDACs are expressed tissue-specifically and can shuttle between the nucleus and the cytoplasm in a phosphorylationdependent manner. HDAC11 is the sole member of the class IV HDAC subfamily. Members of the third class of deacetylases are called sirtuins (Sirt1-7). In contrast to proteins in the other three classes, which are zinc-dependent deacetylases, sirtuins are NAD-dependent enzymes.There is growing consensus that HDACs regulate neuronal survival and that deregulated...

Histone Deacetylase-1 (HDAC1) Is a Molecular Switch between Neuronal Survival and Death

“…Transfection and treatment of neurons were performed as described previously (14,20,21). Briefly, unless stated otherwise, transfections were performed on day 5 after plating for CGNs.…”

A class of their own: exploring the nondeacetylase roles of class IIa HDACs in cardiovascular disease

“…Overexpression of HDAC7 in cultured neurons blocks low potassiuminduced cell death. Interestingly, deletion of the HDAC7 catalytic domain has no effect on HDAC7s neuroprotective effect (48), again giving support to noncanonical/nonenzymatic roles for class IIa HDACs.…”

Human neuronal cells: epigenetic aspects

“…It was shown that HDAC7 translocates into the nucleus where it arbitrates its neuroprotective effects, thereby inhibiting the transcription of proapoptotic mediator c-Jun via the interaction with its promoter. It was also demonstrated that forced HDAC7 expression reversed neuronal cell death in the presence of neurotoxic A β peptides in rodent cortical neurons (107) . There are several beneficial activities associated with HDAC7 expression, particularly increasing the survival of neurons during A β -mediated neurodegeneration seen in AD.…”

“…Knowledge of individual HAT and HDAC functions in the nervous system will prove beneficial in designing appropriate drug targets to ameliorate the incidence of neurodegenerative diseases. Research has flourished in recent years and has shown that certain HDAC isoforms are relatively neuroprotective (66,91,107,108) and inhibition should be avoided. Other HDAC isoforms have shown to selectively mediate neurotoxic effects (94,97,109) , and focus should be put on efforts to downregulate these specific isoforms.…”

“…It is therefore reasonable to conclude that certain HDAC isoforms are required to selectively repress transcriptional processes, which in turn mediate neuronal survival. For example, it was thought that HDAC7 activities are highly neuroprotective during neurodegeneration (107) . It was shown that HDAC7 translocates into the nucleus where it arbitrates its neuroprotective effects, thereby inhibiting the transcription of proapoptotic mediator c-Jun via the interaction with its promoter.…”