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- Table of Contents
Facts about Histone deacetylase 1.
Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and modulates their function.
Human | |
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Gene Name: | HDAC1 |
Uniprot: | Q13547 |
Entrez: | 3065 |
Belongs to: |
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histone deacetylase family |
EC 3.5.1.98; GON-10; HD1; HD1DKFZp686H12203; Histone Deacetylase 1; KDAC1; reduced potassium dependency, yeast homolog-like 1; RPD3L1; RPD3L1RPD3
Mass (kDA):
55.103 kDA
Human | |
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Location: | 1p35.2-p35.1 |
Sequence: | 1; NC_000001.11 (32292083..32333628) |
Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.
Nucleus.
The new therapy option for asthmatic patients is inhibiting HDAC activity. It blocks Th27 differentiation-promoting genes and suppresses proinflammatory genes. This new method is potentially useful in both animal and human models. This hypothesis is still being tested. However, the present study suggests that HDAC inhibition may not be a cure for asthma.
Some researchers have recently discovered that blocking HDAC activity may be a novel therapeutic approach to asthma. This pathway regulates the production cytokines that are involved in the inflammatory process. HDAC inhibitors such as JNJ-263842585 reduce the production of IL-4 and IL-5. The use of these inhibitors may have a prophylactic effect against TDI-induced asthma.
The respiratory epithelium is a physical and an immunological barrier. Asthma may be caused by abnormalities of the airway epithelial Barrier. HDAC inhibitors were found to improve redistribution levels of E-cadherin and b-catenin in mice. Blocking HDAC activity may prove to be an effective therapeutic approach for asthmatic patients.
Previous studies have found that the acetylation of NF-kB by histone deacetylase (HDAC) is important for the development of allergic asthma. However, the exact role of HDAC activity is unknown. However, it has been shown that asthmatic patients who have high levels of reactive oxygen species (ROS), or nitric oxide, are more likely to develop inflammatory disease. Moreover, blockade of HDAC activity inhibits the production of NF-kB.
Recent studies also reveal that RAGE regulates HDAC1 Expression in TDI-Induced Asthma. However, in other studies, the PI3K/AKT pathway is implicated in the regulation of other HDAC subtypes, including HDAC1. Blocking RAGE/HDAC activity may lead towards a breakthrough in asthma treatment. The next step in developing a therapeutic treatment for asthma is to identify the right drug.
This treatment may also have the potential to reduce asthma symptoms. The study was published in The American Academy of Allergy Asthma & Immunology. The results were encouraging, and the authors recommend that patients with asthma be tested for this therapy. But, more research is needed to assess the effects of blocking HDAC activation in asthma. These studies also show the importance of HDAC inhibitors in treating asthma.
In experimental asthma models, blocking HDAC activity from pulmonary epithelial cells can reduce the inflammatory response. A chemical inhibitor is also available to inhibit RAGE activity in asthmatic patients. This inhibitor could also be used to block RAGE signaling. This could be a key role in asthma. If it works, blocking RAGE could be a new therapy for asthmatic patients.
The HDAC1 gene deacetylase inhibitors such as Boster Bio's Vorinostat and entinostat inhibit the expression of pro-inflammatory genes in cancer cells. They also inhibit pancreatic tumor cell growth and stimulate CD8 T-cell function. Their mechanism of action is still not known. However, it seems that Boster Bio's HDAC1 inhibitors regulate the expression of pro-inflammatory genes in human cancer cells.
APC only produces proinflammatory cytokines if the CD4 cell T cells help it produce IFN–g. PanHDAC inhibitors also restored the function of tired CD8 T cells during chronic viral infections. However, no studies have been done to compare the effects of Class 2 HDAC inhibitors on CD4 or CD8 T cells. This means that HDAC inhibitions on these T cells are still not fully understood.
HDAC inhibitors were found to affect both the antitumor immune response as well as the expression of costimulatory molecules in tumor cells. TSA pretreatment resulted in an increase of surface expression for MHCI on cervical cancer cell lines. TSA also enhanced the expression of TAP-2 and TAPasin in the tumor cell line. TSA prevented tumor growth from mice with TAP deficient tumors. Inhibitors also improved the activity and efficiency of adaptive immune effector cells.
HDAC inhibitors, when combined with other immunotherapies increase anti-tumor immune response and block tumor metastasis. This therapy may combine reprogramming cancer's microenvironment, direct killing of tumor cells, and increasing the immune system activity. Immunocombination therapies can also produce more effective anti-tumor reactions. The efficacy of immunocombination therapy will depend on the complementary mechanisms of both modalities.
TDI induced HDAC1 and RAGE activation in asthmatic mice. Moreover E-cadherin redistribution was also increased by TDI-induced asthmatic mice. HDAC inhibitors lowered airway inflammation, airway hyperactivity, and goblet-cell metaplasia. Romidepsin was combined with JNJ-263842585 to reduce airway inflammation and E-cadherin retribution.
The MS-275-induced NRF2 acetylation shows that the inhibitor also affects other types proteins. These HDAC inhibitors also block the deacetylation proteins like p53 or Rb. In this study, lysates from MS-275/NaAsO2-treated CHLA-10 cells were immunoprecipitated using anti-acetyl lysine antibodies and processed for tandem mass spectrometry. The anti-acK antibody helped identify the proteins in the lysates.
In another study, TSA (and Givinostat) decreased the production levels of cytokine-producing cancer cells in tumors. They also decreased the production IL-12 and IL-10. These results demonstrate that the HDAC inhibitors may suppress the inflammatory responses of APCs. Despite these promising results more research is needed to understand how HDAC1 inhibitions inhibit the expression these pro-inflammatory genetics in different types.
Multiple studies have shown inhibition of HDAC activity to inhibit the autoantibody and inflammatory reaction. HDAC inhibitors can also reduce serum levels anti-AChR IIgG2b. HDAC activity inhibition was also linked to the preservation of muscle AChR, and absence of severe disease. These studies also identified specific pathways to control inflammatory reactions.
These researchers used the NanoString nCounter System to profile mRNA expression levels of 770 autoimmune-associated genes. They identified genes whose levels exceeded a threshold. They also used heatmaps and scatter plots to determine gene expression. The expression of genes that are associated with transcription and inflammation was reduced by inhibition of HDAC1 or HDAC2.
Inhibition of HDAC activity decreases IL-6 secretion, an anti-inflammatory cytokine. It also decreases IL-6 mRNA. These results were compared with those obtained using HDAC-i. After 16 h AChR stimulation, PBMCs treated using HDAC-i saw a 50% drop in IL-6 mRNA.
HDAC inhibition is a promising adjunct therapy for MG. HDACs affect gene transcription and the apoptosis pathway. Inhibition of HDACs also inhibits many other proteins, including p53, which results in tumor cell apoptosis. HDAC inhibitors induce double-strand DNA breakage in tumor cells. However, the nongenomic apoptotic effects induced by HDACs treatment are not statistically significant.
Inhibition of HDAC activity inhibits the production of IL-6 and anti-AChR autoantibody in MG. It is not clear what HDAC-i6 inhibitor does. Its action was first demonstrated in collagen-induced joint mice. The effects of SAHA were also observed in splenocyte culture under conditions that promote differentiation and type 17 helper T cell cells.
CD4 cells are more likely to survive when HDAC activity is inhibited. It reduces the growth of pancreatic cancer by increasing CD8 T cell infiltration. It is possible that other HDAC inhibitors may induce immunogenic cell death as well. These findings aren't conclusive. Further research is needed to understand how HDAC inhibitors influence the immune response.
Interestingly, inhibition of HDAC-i also decreased B cell activation. It was associated with a decrease in IL-6 and a decrease in BCMA+ plasma cell counts. These results suggest that IL-6 might play a role independent from IL-21 in promoting the activation of B-cells. The inhibitory effect of HDAC-1i on autoAb production was temporary and was diminished when the treatment was stopped.
Givinostat was a novel HDAC inhibitor that suppressed IL-21 production by human macrophages. It inhibited IL-6, but not IL-21, in AChR stimulation PBMCs. This indicates that HDAC-1i is unable to inhibit IL-21. HDAC inhibition promotes Th27 cell differentiation, but it also inhibits DC and macrophage function.
PMID: 8602529 by Taunton J., et al. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.
PMID: 8646880 by Furukawa Y., et al. Isolation and mapping of a human gene (RPD3L1) that is homologous to RPD3, a transcription factor in Saccharomyces cerevisiae.
*More publications can be found for each product on its corresponding product page