HDAC3

Official Full Name

histone deacetylase 3

Organism

Homo sapiens

GeneID

8841

Background

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]

Synonyms

HD3; RPD3; KDAC3; RPD3-2;

Bio Chemical Class

Carbon-nitrogen hydrolase

Protein Sequence

MAKTVAYFYDPDVGNFHYGAGHPMKPHRLALTHSLVLHYGLYKKMIVFKPYQASQHDMCRFHSEDYIDFLQRVSPTNMQGFTKSLNAFNVGDDCPVFPGLFEFCSRYTGASLQGATQLNNKICDIAINWAGGLHHAKKFEASGFCYVNDIVIGILELLKYHPRVLYIDIDIHHGDGVQEAFYLTDRVMTVSFHKYGNYFFPGTGDMYEVGAESGRYYCLNVPLRDGIDDQSYKHLFQPVINQVVDFYQPTCIVLQCGADSLGCDRLGCFNLSIRGHGECVEYVKSFNIPLLVLGGGGYTVRNVARCWTYETSLLVEEAISEELPYSEYFEYFAPDFTLHPDVSTRIENQNSRQYLDQIRQTIFENLKMLNHAPSVQIHDVPADLLTYDRTDEADAEERGPEENYSRPEAPNEFYDGDHDNDKESDVEI

Open

Disease

Lymphoma, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

Histone deacetylases (HDACs) are enzymes crucial for regulating gene expression by removing acetyl groups from lysine residues on histones and non-histone proteins. Among the HDAC family, HDAC3 is a key player, primarily involved in transcriptional repression, cell cycle regulation, and the progression of various developmental events. The enzyme's ability to alter chromatin structure by deacetylating histones makes it a significant regulator in numerous biological processes. In this review, we explore the essential functions of HDAC3, its involvement in metabolic processes, and its potential as a target for therapeutic interventions.

The Structure and Mechanism of HDAC3

HDAC3, classified as a class I histone deacetylase, shares structural similarities with RPD3, a yeast protein. It possesses a catalytic core domain responsible for its enzymatic activity and unique amino acid residues that distinguish it from other HDACs like HDAC1 and HDAC2. For example, while HDAC1 and HDAC2 contain a glutamate at position 92, HDAC3 has an aspartate at the same position. Such structural differences contribute to the enzyme's unique function, making it a potential target for selective inhibition.

In terms of its enzymatic function, HDAC3 primarily interacts with nuclear receptors and corepressors like NCoR (Nuclear receptor corepressor) and SMRT (Silencing mediator for retinoid and thyroid hormone receptors). This interaction forms a stable complex that facilitates the removal of acetyl groups from histones and non-histone proteins, leading to transcriptional repression. HDAC3 regulates several nuclear receptors, including retinoic acid receptors (RAR) and peroxisome proliferator-activated receptors (PPAR), playing a significant role in controlling gene expression related to metabolic processes and stress responses.

Figure 1 shows how HDAC3 regulates transcription through deacetylation and non-enzymatic interactions, influencing inflammation, heart development, and male fertility. Figure. 1 The enzymatic activity and non-enzymatic functions of HDAC3. (He R, et al., 2023)

HDAC3 in Metabolism and Disease

HDAC3 is deeply involved in metabolic regulation across various tissues. In the liver, for instance, the enzyme plays a role in lipid metabolism. Its deficiency in liver tissue has been linked to steatosis, a condition marked by the accumulation of fat in liver cells, highlighting its importance in maintaining lipid homeostasis. Similarly, in skeletal muscle, HDAC3 regulates glucose metabolism and is essential for maintaining muscle mass and function, particularly during aging.

One of the most intriguing aspects of HDAC3's function is its ability to influence oxidative stress and mitochondrial function. By regulating mitochondrial metabolism, HDAC3 helps control the production of reactive oxygen species (ROS), which can lead to cellular damage if not adequately managed. The enzyme's role in mitochondrial function is complex and tissue-specific, with its absence in brown adipose tissue, for example, resulting in impaired mitochondrial respiration and an increased susceptibility to metabolic diseases.

HDAC3 and Cardiovascular Health

In the heart, HDAC3 is necessary for proper development and function. Mice lacking HDAC3 in their embryonic hearts develop hypertrophic cardiomyopathy, which ultimately leads to death by a few months of age. The enzyme's function in the cardiovascular system extends beyond mere structural integrity; it is also essential for maintaining cardiac energy metabolism. Disruptions in HDAC3 activity can impair the heart's ability to adapt to stress, making it more vulnerable to conditions like cardiomyopathy and heart failure.

HDAC3 and Cancer

Beyond metabolism and development, HDAC3 has a crucial role in cancer biology. By repressing the transcription of tumor suppressor genes, HDAC3 can promote uncontrolled cell proliferation, a hallmark of cancer. Studies have shown that inhibiting HDAC3 can induce cell cycle arrest and apoptosis in cancer cells, offering a potential therapeutic strategy. Inhibitors of HDAC3, such as entinostat, are currently being explored in clinical trials for their ability to treat various cancers, including advanced breast cancer.

Targeting HDAC3 for Therapeutic Purposes

Given its involvement in metabolic disorders, cancer, and other diseases, HDAC3 presents a promising target for drug development. Several HDAC inhibitors are already in clinical development, aiming to exploit the enzyme's role in gene regulation. Entinostat, which selectively inhibits HDAC1, HDAC2, and HDAC3, has shown potential in treating breast cancer. Other dual-target HDAC inhibitors, such as CUDC-907, which also targets the PI3K pathway, are being investigated for their ability to enhance therapeutic efficacy in cancer treatment.

Furthermore, the enzyme's involvement in metabolic diseases, such as obesity and diabetes, suggests that modulating HDAC3 activity could help manage these conditions. Research into HDAC3 inhibitors is ongoing, to develop drugs that can selectively target this enzyme without affecting other HDACs, thereby reducing side effects.

References:

Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713. Published 2014 Apr 1.
Paluvai H, Shanmukha KD, Tyedmers J, et al. Insights into the function of HDAC3 and NCoR1/NCoR2 co-repressor complex in metabolic diseases. Front Mol Biosci. 2023;10:1190094.
He R, Liu B, Geng B, et al. The role of HDAC3 and its inhibitors in regulation of oxidative stress and chronic diseases. Cell Death Discov. 2023;9(1):131.

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