HDAC1

Official Full Name

histone deacetylase 1

Organism

Homo sapiens

GeneID

3065

Background

Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family and is a component of the histone deacetylase complex. It also interacts with retinoblastoma tumor-suppressor protein and this complex is a key element in the control of cell proliferation and differentiation. Together with metastasis-associated protein-2, it deacetylates p53 and modulates its effect on cell growth and apoptosis. [provided by RefSeq, Jul 2008]

Synonyms

HD1; RPD3; KDAC1; GON-10; RPD3L1;

Bio Chemical Class

Carbon-nitrogen hydrolase

Protein Sequence

MAQTQGTRRKVCYYYDGDVGNYYYGQGHPMKPHRIRMTHNLLLNYGLYRKMEIYRPHKANAEEMTKYHSDDYIKFLRSIRPDNMSEYSKQMQRFNVGEDCPVFDGLFEFCQLSTGGSVASAVKLNKQQTDIAVNWAGGLHHAKKSEASGFCYVNDIVLAILELLKYHQRVLYIDIDIHHGDGVEEAFYTTDRVMTVSFHKYGEYFPGTGDLRDIGAGKGKYYAVNYPLRDGIDDESYEAIFKPVMSKVMEMFQPSAVVLQCGSDSLSGDRLGCFNLTIKGHAKCVEFVKSFNLPMLMLGGGGYTIRNVARCWTYETAVALDTEIPNELPYNDYFEYFGPDFKLHISPSNMTNQNTNEYLEKIKQRLFENLRMLPHAPGVQMQAIPEDAIPEESGDEDEDDPDKRISICSSDKRIACEEEFSDSEEEGEGGRKNSSNFKKAKRVKTEDEKEKDPEEKKEVTEEEKTKEEKPEAKGVKEEVKLA

Open

Disease

Acute myeloid leukaemia, Ataxic disorder, Breast cancer, Cerebral ischaemia, Cerebral ischaemic stroke, Colorectal cancer, Diffuse large B-cell lymphoma, Intracranial injury, Ischaemic/haemorrhagic stroke, Leukaemia, Liver cancer, Lung cancer, Lymphoma, Mature T-cell lymphoma, Melanoma, Metabolism inborn error, Mood disorder, Multiple myeloma, Muscular dystrophy, Mycosis fungoides, Myeloproliferative neoplasm, Neuroendocrine carcinoma, Ovarian cancer, Renal cell carcinoma, Sickle-cell disorder, Solid tumour/cancer, Thrombocytosis, Type 2 diabetes mellitus

Approved Drug

4 +

Clinical Trial Drug

20 +

Discontinued Drug

4 +

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Detailed Information

A member of the Histone Deacetylases (HDACs) family, HDAC1 mostly regulates chromatin shape and gene expression by removing acetyl groups from histones. HDAC1's catalytic domain interacts with a zinc ion; its catalytic activity relies on the consistent interaction with this zinc ion. The structural characteristics of HDAC1 let it interact with other proteins in several ways, hence enabling it to have regulatory effects in diverse cellular contexts. Interactions with many transcription factors and co-repressors help it to deacetylate. These interactions control several important cellular processes by use of non-histone substrates as well as histones.

Figure 1 illustrates the regulatory role of Histone Deacetylase 1 (HDAC1) in both histone and non-histone proteins. Figure 1. Histone deacetylase 1 (HDAC1) regulates both histone and non-histone proteins. (Seto E, et al., 2014)

Role of HDAC1

Regulating the cell cycle depends much on HDAC1. HDAC1 regulates p21 production in endothelial cells by deacetylating p53, hence regulating or blocking cell cycle movement. Specifically, HDAC1 deacetylates p53 by interacting with proteins including MTA2, therefore suppressing cell cycle progression. The connection between HDAC1 and p53 is strengthened by environmental stressors like shear stress, which causes p53 deacetylation and p21 expression activation. Not just for regular cell division but also for control under environmental stress, this mechanism is essential.

A process intimately related to HDAC1 activity, cells' failure to sustain efficient division causes cellular aging. Research indicates that HDAC1 has two roles in endothelial cell aging. Under some circumstances, lower HDAC1 activity is strongly linked to mitochondrial dysfunction, cellular aging, and lower antioxidant capability. HDAC1 expression in endothelial cells exposed to irradiation or high-passage drops considerably, therefore encouraging cellular aging. On the other hand, endothelial cell function is maintained by modest HDAC1 activity. HDAC1 can control mitochondrial activity and stop age-related drop in cellular function by deacetylating PGC1α.

Key actors in inflammatory reactions are endothelial cells; HDAC1 has a major regulatory influence during these events. By deacetylating transcription factors including NF-\u03baB, HDAC1 not only inhibits the production of cytokines and cell adhesion molecules but also controls endothelial cell responses to inflammatory stimuli. HDAC1, for example, interacts with the p65 component of NF-kB to decrease its transcriptional activity and hence lower endothelial inflammation. Particularly in pathological circumstances like atherosclerosis, where lower HDAC1 expression is linked with heightened inflammatory responses, higher adhesion molecules, and arterial damage, this process is crucial.

Repairing tissue injury is influenced by the process of generating new blood vessels known as angiogenesis. HDAC1's function in this setting is very complicated. Most studies show that HDAC1's anti-proliferative activities in endothelial cells are directly linked to its prevention of angiogenesis. By deacetylating transcription factors like Bach1, HDAC1 reduces the production of angiogenesis-related cytokines like IL-8 and VEGF. Furthermore, HDAC1's interaction with NF-κB also regulates VEGF expression, further modulating angiogenesis. Some research, nevertheless, indicates that under certain conditions HDAC1 could encourage angiogenesis by changing its subcellular location. For instance, shear stress causes HDAC1 phosphorylation to move it from the nucleus to the cytoplasm, hence increasing MMP14 activity and encouraging vessel formation.

HDAC1 and Cardiovascular Diseases

Given HDAC1's crucial role in endothelial cell function, its relationship with cardiovascular diseases has drawn significant attention. HDAC1 is involved in the onset and development of various cardiovascular diseases by regulating inflammatory responses, antioxidant reactions, and endothelial function. For instance, under conditions like hyperglycemia or atherosclerosis, decreased HDAC1 expression leads to the suppression of antioxidant genes, thereby contributing to endothelial dysfunction and atherosclerosis progression. Research also suggests that selective inhibition of HDAC1 might offer a novel strategy for treating these diseases.

HDAC1 as a Therapeutic Target

Already used in cancer therapy, HDAC1 inhibition has led to the approval of HDAC inhibitors (HDACi) for certain hematological cancers. More studies on HDAC1 activities are prompting more scientists to investigate its possible use as a therapeutic target for different illnesses, particularly for neurological and cardiovascular ailments. Though none are particular HDAC1 inhibitors now available, several medications aimed at HDAC1 have shown effectiveness in clinical studies. For instance, studies for hematological malignancies have shown therapeutic promise for MS-275 and other targeted HDAC1 inhibitors, which may guide future therapy plans.

References:

Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713.
Dunaway LS, Pollock JS. HDAC1: an environmental sensor regulating endothelial function. Cardiovasc Res. 2022;118(8):1885-1903.
Ma P, Schultz RM. HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation. Cell Death Differ. 2016;23(7):1119-1127.

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