Regulation of Histone Deacetylase 6 (HDAC6) Activity via S-Nitrosylation

Okuda, Kosaku; Ito, Akihiro; Uehara, Takashi

doi:10.1016/j.freeradbiomed.2016.10.113

Cited by 5 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This could be explained by multiple factors. First, HDAC6 is regulated by nitrosylation (Okuda et al, 2015). Perhaps more importantly, only membrane tubulin (particularly lipid-raft tubulin) was affected, as the total degree of tubulin acetylation was constant among all groups.…”

Section: Discussionmentioning

confidence: 99%

Membrane-Associated α-Tubulin Is Less Acetylated in Postmortem Prefrontal Cortex from Depressed Subjects Relative to Controls: Cytoskeletal Dynamics, HDAC6, and Depression

et al. 2020

View full text Add to dashboard Cite

Cytoskeletal proteins and post-translational modifications play a role in mood disorders. Post-translational modifications of tubulin also alter microtubule dynamics. Furthermore, tubulin interacts closely with Ga s , the G-protein responsible for activation of adenylyl cyclase. Postmortem tissue derived from depressed suicide brain showed increased Ga s in lipid-raft domains compared with normal subjects. Ga s , when ensconced in lipid rafts, couples less effectively with adenylyl cyclase to produce cAMP, and this is reversed by antidepressant treatment. A recent in vitro study demonstrated that tubulin anchors Ga s to lipid rafts and that increased tubulin acetylation (due to HDAC6 inhibition) and antidepressant treatment decreased the proportion of Ga s complexed with tubulin. This suggested that deacetylated-tubulin might be more prevalent in depression. This study examined tubulin acetylation in whole-tissue homogenate, plasma membrane, and lipid-raft membrane domains in tissue from normal control subjects, depressed suicides, and depressed nonsuicides (human males/females). While tissue homogenate showed no changes in tubulin acetylation between control, depressed suicides, and depressed nonsuicides, plasma membrane-associated tubulin showed significant decreases in acetylation from depressed suicides and depressed nonsuicides compared with controls. No change was seen in expression of the enzymes responsible for tubulin acetylation or deacetylation. These data suggest that, during depression, membrane-localized tubulin maintains a lower acetylation state, permitting increased sequestration of Ga s in lipid-raft domains, where it is less likely to couple to adenylyl cyclase for cAMP production. Thus, membrane tubulin may play a role in mood disorders, which could be exploited for diagnosis and treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Membrane-Associated α-Tubulin Is Less Acetylated in Postmortem Prefrontal Cortex from Depressed Subjects Relative to Controls: Cytoskeletal Dynamics, HDAC6, and Depression

et al. 2020

View full text Add to dashboard Cite

show abstract

“…To explain the observed NO-mediated histone hyperacetylation, we hypothesized that NO might directly target HDACs and inhibit their activity, a mechanism that has been described for some mammalian HDACs (Colussi et al, 2008;Nott et al, 2008;Feng et al, 2011;Okuda et al, 2015). To determine the effect of NO on histone deacetylase activity, a commercial fluorescence-based HDAC assay was modified to be used in protoplasts.…”

Section: Hdac Activity Is Inhibited By Redox Modificationsmentioning

confidence: 99%

“…HDAC2 is nitrosylated at two Cys residues after stimulation of neurons with brain-derived neurotrophic factor, which leads to its dissociation from chromatin and subsequent chromatin remodeling at genes involved in neuronal development (Nott et al, 2008). HDAC6, which mainly deacetylates cytosolic a-tubulin, is S-nitrosylated by cytokine-induced NO production, resulting in the inhibition of this enzyme (Okuda et al, 2015). Finally, HDAC8 was demonstrated to be modified by NO in vitro (Feng et al, 2011).…”

Section: Redox Regulation Of Hdacsmentioning

confidence: 99%

Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases

et al. 2016

View full text Add to dashboard Cite

Histone acetylation, which is an important mechanism to regulate gene expression, is controlled by the opposing action of histone acetyltransferases and histone deacetylases (HDACs). In animals, several HDACs are subjected to regulation by nitric oxide (NO); in plants, however, it is unknown whether NO affects histone acetylation. We found that treatment with the physiological NO donor S-nitrosoglutathione (GSNO) increased the abundance of several histone acetylation marks in Arabidopsis (Arabidopsis thaliana), which was strongly diminished in the presence of the NO scavenger 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. This increase was likely triggered by NO-dependent inhibition of HDAC activity, since GSNO and S-nitroso-N-acetyl-DL-penicillamine significantly and reversibly reduced total HDAC activity in vitro (in nuclear extracts) and in vivo (in protoplasts). Next, genome-wide H3K9/14ac profiles in Arabidopsis seedlings were generated by chromatin immunoprecipitation sequencing, and changes induced by GSNO, GSNO/2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide or trichostatin A (an HDAC inhibitor) were quantified, thereby identifying genes that display putative NO-regulated histone acetylation. Functional classification of these genes revealed that many of them are involved in the plant defense response and the abiotic stress response. Furthermore, salicylic acid, which is the major plant defense hormone against biotrophic pathogens, inhibited HDAC activity and increased histone acetylation by inducing endogenous NO production. These data suggest that NO affects histone acetylation by targeting and inhibiting HDAC complexes, resulting in the hyperacetylation of specific genes. This mechanism might operate in the plant stress response by facilitating the stress-induced transcription of genes.

show abstract

“…Alternatively, methods to target the upstream regulators of HDAC6 could indirectly decrease its protein levels and reduce deacetylase and E3 ubiquitin ligase activity. For instance, tamoxifen treatment of MCF-7 breast cancer cells prevented estradiol-stimulated HDAC6 accumulation and α-tubulin deacetylation (45), and nitric oxide (NO) is able to increase the acetylation of αtubulin in in A549 cells by preventing the essential S-nitrosylation of HDAC6 (46). More directly, Cullin 3SPOP has been reported to destabilize HDAC6 via polyubiquitination, and this interaction has suggested that SPOP serves a tumor suppressor function through this mechanism (47).…”

Section: Discussionmentioning

confidence: 99%

HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

Moses

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

We previously discovered that HDAC6 regulates the DNA damage response via modulating the homeostasis of a DNA mismatch repair protein, MSH2, through HDAC6’s ubiquitin E3 ligase activity. Here, we have reported HDAC6’s second E3 ligase substrate, a critical cell cycle checkpoint protein, Chk1. We have found that HDAC6 and Chk1 directly interact, and that HDAC6 ubiquitinates Chk1 in vivo. Typical Chk1 protein levels fluctuate, peaking at G2 and subsequently resolving via the ubiquitin-proteasome pathway. However, in HDAC6 knockdown cells, Chk1 is constitutively active and fails to resolve post-ionizing radiation (IR), leading to increased radiation sensitivity. Upon IR treatment, a greater proportion of HDAC6 knockdown cells accumulated at G2/M phase when compared with control cells. Depletion or inhibition of Chk1 in HDAC6 knockdown cells renders those cells radiosensitive, suggesting that persistently high level of Chk1 could lead cells to arrest at G2/M phase and eventually, apoptosis. Clinically, we found that high levels of phosphorylated Chk1 (p-Ser317) are associated with a better overall survival in a cohort of non-small cell lung cancer (NSCLC) patients, suggesting a link between active Chk1 and lung cancer development. Overall, our results highlight a novel mechanism of Chk1 regulation at the protein level, and a possible strategy for sensitizing NSCLC to radiation via inhibiting the activity of HDAC6’s E3 ligase.

show abstract

Regulation of Histone Deacetylase 6 (HDAC6) Activity via S-Nitrosylation

Cited by 5 publications

References 0 publications

Membrane-Associated α-Tubulin Is Less Acetylated in Postmortem Prefrontal Cortex from Depressed Subjects Relative to Controls: Cytoskeletal Dynamics, HDAC6, and Depression

Membrane-Associated α-Tubulin Is Less Acetylated in Postmortem Prefrontal Cortex from Depressed Subjects Relative to Controls: Cytoskeletal Dynamics, HDAC6, and Depression

Nitric Oxide Modulates Histone Acetylation at Stress Genes by Inhibition of Histone Deacetylases

HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1

Contact Info

Product

Resources

About