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HDAC4

Official Full Name
histone deacetylase 4
Organism
Homo sapiens
GeneID
9759
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 class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]
Synonyms
HD4; AHO3; BDMR; HDACA; HA6116; HDAC-4; HDAC-A; NEDCHF; NEDCHID;
Bio Chemical Class
Carbon-nitrogen hydrolase
Protein Sequence
MSSQSHPDGLSGRDQPVELLNPARVNHMPSTVDVATALPLQVAPSAVPMDLRLDHQFSLPVAEPALREQQLQQELLALKQKQQIQRQILIAEFQRQHEQLSRQHEAQLHEHIKQQQEMLAMKHQQELLEHQRKLERHRQEQELEKQHREQKLQQLKNKEKGKESAVASTEVKMKLQEFVLNKKKALAHRNLNHCISSDPRYWYGKTQHSSLDQSSPPQSGVSTSYNHPVLGMYDAKDDFPLRKTASEPNLKLRSRLKQKVAERRSSPLLRRKDGPVVTALKKRPLDVTDSACSSAPGSGPSSPNNSSGSVSAENGIAPAVPSIPAETSLAHRLVAREGSAAPLPLYTSPSLPNITLGLPATGPSAGTAGQQDAERLTLPALQQRLSLFPGTHLTPYLSTSPLERDGGAAHSPLLQHMVLLEQPPAQAPLVTGLGALPLHAQSLVGADRVSPSIHKLRQHRPLGRTQSAPLPQNAQALQHLVIQQQHQQFLEKHKQQFQQQQLQMNKIIPKPSEPARQPESHPEETEEELREHQALLDEPYLDRLPGQKEAHAQAGVQVKQEPIESDEEEAEPPREVEPGQRQPSEQELLFRQQALLLEQQRIHQLRNYQASMEAAGIPVSFGGHRPLSRAQSSPASATFPVSVQEPPTKPRFTTGLVYDTLMLKHQCTCGSSSSHPEHAGRIQSIWSRLQETGLRGKCECIRGRKATLEELQTVHSEAHTLLYGTNPLNRQKLDSKKLLGSLASVFVRLPCGGVGVDSDTIWNEVHSAGAARLAVGCVVELVFKVATGELKNGFAVVRPPGHHAEESTPMGFCYFNSVAVAAKLLQQRLSVSKILIVDWDVHHGNGTQQAFYSDPSVLYMSLHRYDDGNFFPGSGAPDEVGTGPGVGFNVNMAFTGGLDPPMGDAEYLAAFRTVVMPIASEFAPDVVLVSSGFDAVEGHPTPLGGYNLSARCFGYLTKQLMGLAGGRIVLALEGGHDLTAICDASEACVSALLGNELDPLPEKVLQQRPNANAVRSMEKVMEIHSKYWRCLQRTTSTAGRSLIEAQTCENEEAETVTAMASLSVGVKPAEKRPDEEPMEEEPPL
Open
Disease
Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
0
Discontinued Drug
0

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Detailed Information

Histone deacetylases (HDACs) are enzymes that play a key role in regulating gene expression by removing acetyl groups from histone proteins, a process critical for maintaining cellular functions like transcription, differentiation, and proliferation. HDAC4 is a Class IIa HDAC that impacts cell cycle control, muscle development, and neural function. It is one of 18 known HDACs in mammals. Class I HDACs are mostly found in the nucleus, but HDAC4 moves back and forth between the nucleus and the cytoplasm based on certain signals, especially those that control development and stress reactions.

Figure 1 illustrates the mechanisms governing HDAC4's shuttling between the nucleus and cytoplasm, highlighting its phosphorylation by kinases like CaMK, oxidation of specific cysteine residues, and N-terminal cleavage as key regulators of its subcellular localization and functional activity.Figure 1. The scheme of HDAC4 partitioning between the nucleus and cytoplasm. (Huang C, et al., 2022)

Role in Transcriptional Regulation

By removing a lysine group from histones and other proteins, HDAC4 prevents gene expression. In muscle cells, this protein is rather significant as it interacts with transcription factors including MEF2 to govern the growth of muscle stem cells. HDAC4 inhibits the synthesis of muscle-specific genes via linking to MEF2C and MEF2D.  This keeps stem cells from differentiating. Muscle development and repair depend much on this procedure. In neurons, which are essential for memory and learning, HDAC4 regulates synaptic plasticity and long-term potentiation (LTP).

HDAC4's Subcellular Localization and Regulation

The position of HDAC4 within cells is closely linked to its activity and is controlled by changes that happen after translation, specifically phosphorylation. Although HDAC4 is normally found in the cytoplasm of neurons, it moves to the nucleus when activated by kinases like CaMKII to stop transcription. HDAC4, on the other hand, is found in the center of myoblasts (muscle cells) and stops muscle growth. This shuttling system is very important for controlling how cells react to messages during stress, differentiation, and development.

HDAC4 and its Role in Disease

Extensive research has been done on HDAC4's involvement in many diseases, including dementia, cardiovascular disorders, and cancer. It regulates numerous molecular-level biological processes; when it malfunctions, it may aggravate illnesses.

Mainly neurological disorders like Alzheimer's and Huntington's, HDAC4 has been connected to central nervous system issues. In these cases, the survival and function of neurons are impacted by HDAC4's deacetylase activity. Particularly, it is important for learning and memory as it regulates synaptic change and gene expression in neurons. Studies have shown that in neurological conditions HDAC4 malfunctioning may cause neuronal death and cognitive decline.

People with Alzheimer's also have more HDAC4. Several studies indicate that inhibiting HDAC4 might enhance brain function and reduce amyloid-induced inflammation. The concept that HDAC4 inhibitors may protect neurons is being researched in fascinating ways.

Heart problems very much depend on HDAC4, particularly vascular inflammation, smooth muscle cell growth, and arterial stiffening. Research has shown that HDAC4 may regulate the proliferation of vascular smooth muscle cells, a fundamental process in the formation of atherosclerosis and high blood pressure. One approach it does this is by regulating several signaling pathways including the MEF2 pathway, which regulates arterial remodeling.

Phosphorylation of HDAC4 by kinases such as CaMKII activates it and promotes inflammatory response and aberrant blood vessel development. Stopping HDAC4 either with medications or by altering its genes has been proven in animal models of high blood pressure to lower the development of vascular smooth muscle cells and the inflammatory response. HDAC4 could thus be a target for therapy to improve heart health and assist manage arterial diseases.

Studies show HDAC4 regulates cancer cell growth, invasion, and dissemination to other body areas. Studies have shown that HDAC4 may modify the acetylation condition of important transcription factors, therefore influencing the movement of cancer cells. In breast cancer, for instance, HDAC4 regulates ESR1 synthesis, which may affect the speed of tumor growth and the efficacy of hormone therapies. Targeting HDAC4 might help to manage epigenetics and thus help to cure certain cancers.

Potential Therapeutic Implications of HDAC4 Inhibition

HDAC4 has great potential as a therapeutic target for numerous diseases—including malignancies, neurological disorders, and cardiac diseases—since it is so crucial for regulating gene expression, cell division, and the progression of disease.

Currently, not much research is being done to create particular HDAC4 medications. Stronger HDAC inhibitors, such as vorinostat and romidepsin, which act against more than one kind of HDAC, may also affect how HDAC4 operates. These inhibitors have shown potential in treating cancer, and future studies might demonstrate that they can also be utilized to target HDAC4 directly.

Several studies have also investigated the uses of class IIa HDAC inhibitors for vascular diseases. Blocking HDAC4 and related kinds might help to reduce vascular inflammation, smooth muscle cell growth, and other harmful mechanisms causing heart disease. This particular blockade could result in a more concentrated treatment strategy with fewer of the negative effects associated with more general HDAC blocking.

HDAC4 is an even more fascinating target for treatment given its role in age-related disorders including neurodegeneration, vascular stiffness, and high blood pressure. HDAC4 contributes to the deterioration of vascular aging and failure as one age, which is intimately related to long-term disorders including diabetes and atherosclerosis. Inhibiting HDAC4 could be a novel approach to delay aging and prevent or reduce age-related disorders.

Researchers are also looking at how HDAC4 contributes to reactive stress. Targeting HDAC4 to alter ROS levels might be a good approach to treat heart disease and dementia as oxidative stress is a major cause.

References:

  1. 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.
  2. Huang C, Lin Z, Liu X, et al. HDAC4 Inhibitors as Antivascular Senescence Therapeutics. Oxid Med Cell Longev. 2022;2022:3087916. Published 2022 Jun 29.
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