HDAC2

Official Full Name

histone deacetylase 2

Organism

Homo sapiens

GeneID

3066

Background

This gene product belongs to the histone deacetylase family. Histone deacetylases act via the formation of large multiprotein complexes, and are responsible for the deacetylation of lysine residues at the N-terminal regions of core histones (H2A, H2B, H3 and H4). This protein forms transcriptional repressor complexes by associating with many different proteins, including YY1, a mammalian zinc-finger transcription factor. Thus, it plays an important role in transcriptional regulation, cell cycle progression and developmental events. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

Synonyms

HD2; RPD3; YAF1; KDAC2;

Bio Chemical Class

Carbon-nitrogen hydrolase

Protein Sequence

MAYSQGGGKKKVCYYYDGDIGNYYYGQGHPMKPHRIRMTHNLLLNYGLYRKMEIYRPHKATAEEMTKYHSDEYIKFLRSIRPDNMSEYSKQMQRFNVGEDCPVFDGLFEFCQLSTGGSVAGAVKLNRQQTDMAVNWAGGLHHAKKSEASGFCYVNDIVLAILELLKYHQRVLYIDIDIHHGDGVEEAFYTTDRVMTVSFHKYGEYFPGTGDLRDIGAGKGKYYAVNFPMRDGIDDESYGQIFKPIISKVMEMYQPSAVVLQCGADSLSGDRLGCFNLTVKGHAKCVEVVKTFNLPLLMLGGGGYTIRNVARCWTYETAVALDCEIPNELPYNDYFEYFGPDFKLHISPSNMTNQNTPEYMEKIKQRLFENLRMLPHAPGVQMQAIPEDAVHEDSGDEDGEDPDKRISIRASDKRIACDEEFSDSEDEGEGGRRNVADHKKGAKKARIEEDKKETEDKKTDVKEEDKSKDNSGEKTDTKGTKSEQLSNP

Open

Disease

Eczema, Lymphoma, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

HDAC2 (Histone Deacetylase 2) is a critical member of the histone deacetylase (HDAC) family, which plays an essential role in cellular regulation. Discovered in 1996, HDAC2 shares a high degree of sequence homology with its counterpart, HDAC1, and, like HDAC1, functions by removing acetyl groups from lysine residues in histones, leading to transcriptional repression. However, HDAC2 exhibits specific roles in certain cellular processes and neuronal functions, particularly in neural differentiation and synaptic plasticity. It is crucial for understanding both developmental processes and disease mechanisms, including neurodegenerative disorders and cancer.

Function and Mechanisms of Action

HDAC2 is primarily located in the cell nucleus, where it functions as a key transcriptional repressor. It is recruited to specific DNA promoters, often working in concert with transcriptional co-repressors such as N-CoR (Nuclear Receptor Co-Repressor) to repress gene expression. By removing acetyl groups from histones, HDAC2 enables the condensation of chromatin, thus preventing transcription. This action is essential in regulating the expression of genes involved in various cellular processes, including stress response and differentiation.

Apart from histones, HDAC2 also acts on non-histone proteins, such as p53, a tumor suppressor. Deacetylation of non-histone proteins by HDAC2 influences their activity, stability, and function. For example, p53 deacetylation by HDAC2 leads to its degradation, impacting its tumor-suppressing function. HDAC2's involvement in cellular mechanisms extends to the regulation of gene expression, both in response to external signals and during stress conditions. This regulation is particularly significant in processes like cellular differentiation and synaptic plasticity.

HDAC2 in Neuronal Function and Memory

The role of HDAC2 in the central nervous system (CNS) is particularly noteworthy. HDAC2 is involved in neural differentiation, synaptic plasticity, and memory formation. It regulates the expression of genes related to neuronal growth and survival. By controlling the acetylation status of histones in the chromatin, HDAC2 plays a critical role in maintaining the balance of gene expression that is necessary for proper neuronal function.

Notably, studies have shown that a reduction in HDAC2 expression enhances memory and cognitive function, suggesting that this protein is a potential therapeutic target for neurodegenerative diseases, including Alzheimer's disease. Since HDAC2 modulates key genes involved in neuronal plasticity and survival, its regulation could hold promise for therapeutic strategies aimed at enhancing cognitive function or slowing disease progression in conditions like Alzheimer's.

HDAC2 and Cancer

In cancer, HDAC2 plays a pivotal role in promoting tumorigenesis. HDAC2 is upregulated in various cancers, and it contributes to the silencing of tumor suppressor genes that control cell cycle arrest and apoptosis. This silencing effect facilitates uncontrolled cell growth and survival, leading to cancer development. As such, HDAC2 represents a promising target for cancer therapy.

Figure 1 illustrates the mechanism by which HDAC2 promotes cancer cell proliferation through the regulation of processes like EMT, invasion/migration, apoptosis, cell cycle, signaling, cancer stemness, immune evasion, and cellular proliferation. Figure 1. Mechanism of HDAC2-promoted cancer cell proliferation. (Jo H, et al., 2023)

The inhibition of HDAC2 has been shown to reactivate silenced genes involved in tumor suppression, providing a potential strategy for restoring normal cell cycle control and inducing cancer cell death. Inhibiting HDAC2 may help reactivate the expression of these key genes, thus offering therapeutic benefits, especially in cancers where these genes are inappropriately silenced.

Drug Development and Clinical Applications

While HDAC2 has not yet been specifically targeted in drug development, many HDAC inhibitors currently in use also inhibit HDAC2 activity. For example, non-selective HDAC inhibitors, such as romidepsin, vorinostat, and belinostat, are FDA-approved for treating peripheral T-cell lymphoma and cutaneous T-cell lymphoma, among other hematologic cancers. These drugs inhibit multiple HDAC family members, including HDAC2, thereby reducing tumor progression.

More selectively, Entinostat, an HDAC inhibitor with a higher specificity for HDAC1, HDAC2, and HDAC3, is currently undergoing clinical trials, particularly in the treatment of advanced breast cancer. Preliminary results suggest that Entinostat's ability to target HDAC2 may improve therapeutic outcomes, especially when combined with other treatment modalities like endocrine therapy.

References:

Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713.
Ma P, Schultz RM. HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation. Cell Death Differ. 2016;23(7):1119-1127.
Jo H, Shim K, Kim HU, et al. HDAC2 as a target for developing anti-cancer drugs. Comput Struct Biotechnol J. 2023;21:2048-2057.

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