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Histone deacetylase
Histone deacetylase
Histone deacetylase
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Histone deacetylase
Catalytic domain of human histone deacetylase 4 with bound inhibitor. PDB rendering based on 2vqj.[1]
Identifiers
EC no.3.5.1.98
CAS no.9076-57-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
Histone deacetylase superfamily
Identifiers
SymbolHist_deacetyl
PfamPF00850
InterProIPR000286
SCOP21c3s / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins.[2] HDACs allow histones to wrap the DNA more tightly.[3] This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins.[4] In general, they suppress gene expression.[5]

HDAC super family

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Together with the acetylpolyamine amidohydrolases and the acetoin utilization proteins, the histone deacetylases form an ancient protein superfamily known as the histone deacetylase superfamily.[6]

Classes of HDACs in higher eukaryotes

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HDACs, are classified in four classes depending on sequence homology to the yeast original enzymes and domain organization:[7]

HDAC classification in higher eukaryotes
Class Members Catalytic sites Subcellular localization Tissue distribution Substrates Binding partners Knockout phenotype
I HDAC1 1 Nucleus Ubiquitous Androgen receptor, SHP, p53, MyoD, E2F1, STAT3 – Embryonic lethal, increased histone acetylation, increase in p21 and p27
HDAC2 1 Nucleus Ubiquitous Glucocorticoid receptor, YY1, BCL6, STAT3 – Cardiac defect
HDAC3 1 Nucleus Ubiquitous SHP, YY1, GATA1, RELA, STAT3, MEF2D NCOR1[8] –
HDAC8 1 Nucleus/cytoplasm Ubiquitous? – EST1B –
IIA HDAC4 1 Nucleus / cytoplasm heart, skeletal muscle, brain GCMA, GATA1, HP1 RFXANK Defects in chondrocyte differentiation
HDAC5 1 Nucleus / cytoplasm heart, skeletal muscle, brain GCMA, SMAD7, HP1 REA, estrogen receptor Cardiac defect
HDAC7 1 Nucleus / cytoplasm / mitochondria heart, skeletal muscle, pancreas, placenta PLAG1, PLAG2 HIF1A, BCL6, endothelin receptor, ACTN1, ACTN4, androgen receptor, Tip60 Maintenance of vascular integrity, increase in MMP10
HDAC9 1 Nucleus / cytoplasm brain, skeletal muscle – FOXP3 Cardiac defect
IIB HDAC6 2 Mostly cytoplasm heart, liver, kidney, placenta α-Tubulin, HSP90, SHP, SMAD7 RUNX2 –
HDAC10 1 Mostly cytoplasm liver, spleen, kidney – – –
III sirtuins in mammals (SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7) – – – – – –
Sir2 in the yeast S. cerevisiae – – – – – –
IV HDAC11 2 Nucleus / cytoplasm brain, heart, skeletal muscle, kidney – – –

HDAC (except class III) contain zinc and are known as Zn2+-dependent histone deacetylases.[9] They feature a classical arginase fold and are structurally and mechanistically distinct from sirtuins (class III), which fold into a Rossmann architecture and are NAD+ dependent.[10]

Subtypes

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HDAC proteins are grouped into four classes (see above) based on function and DNA sequence similarity. Class I, II and IV are considered "classical" HDACs whose activities are inhibited by trichostatin A (TSA) and have a zinc dependent active site, whereas Class III enzymes are a family of NAD+-dependent proteins known as sirtuins and are not affected by TSA.[11] Homologues to these three groups are found in yeast having the names: reduced potassium dependency 3 (Rpd3), which corresponds to Class I; histone deacetylase 1 (hda1), corresponding to Class II; and silent information regulator 2 (Sir2), corresponding to Class III. Class IV contains just one isoform (HDAC11), which is not highly homologous with either Rpd3 or hda1 yeast enzymes,[12] and therefore HDAC11 is assigned to its own class. The Class III enzymes are considered a separate type of enzyme and have a different mechanism of action; these enzymes are NAD+-dependent, whereas HDACs in other classes require Zn2+ as a cofactor.[13]

Evolution

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HDACs are conserved across evolution, showing orthologs in all eukaryotes and even in Archaea. All upper eukaryotes, including vertebrates, plants and arthropods, possess at least one HDAC per class, while most vertebrates carry the 11 canonical HDACs, with the exception of bone fish, which lack HDAC2 but appears to have an extra copy of HDAC11, dubbed HDAC12. Plants carry additional HDACs compared to animals, putatively to carry out the more complex transcriptional regulation required by these sessile organisms. HDACs appear to be deriving from an ancestral acetyl-binding domain, as HDAC homologs have been found in bacteria in the form of Acetoin utilization proteins (AcuC) proteins.[3]

Topological phylogenetic tree representation of 226 members of the HDAC protein family.[3]

Subcellular distribution

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Within the Class I HDACs, HDAC1, 2, and 3 are found primarily in the nucleus, whereas HDAC8 is found in both the nucleus and the cytoplasm, and is also membrane-associated. Class II HDACs (HDAC4, 5, 6, 7 9, and 10) are able to shuttle in and out of the nucleus, depending on different signals.[14][15]

HDAC6 is a cytoplasmic, microtubule-associated enzyme. HDAC6 deacetylates tubulin, Hsp90, and cortactin, and forms complexes with other partner proteins, and is, therefore, involved in a variety of biological processes.[16]

Function

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Histone modification

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Histone tails are normally positively charged due to amine groups present on their lysine and arginine amino acids. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. Acetylation, which occurs normally in a cell, neutralizes the positive charges on the histone by changing amines into amides and decreases the ability of the histones to bind to DNA. This decreased binding allows chromatin expansion, permitting genetic transcription to take place. Histone deacetylases remove those acetyl groups, increasing the positive charge of histone tails and encouraging high-affinity binding between the histones and DNA backbone. The increased DNA binding condenses DNA structure, preventing transcription.

Histone deacetylase is involved in a series of pathways within the living system. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG), these are:

Some activation signals on a nucleosome: Nucleosomes consist of four pairs of histone proteins in a tightly assembled core region plus up to 30% of each histone remaining in a loosely organized tail (only one tail of each pair is shown). DNA is wrapped around the histone core proteins in chromosomes. The lysines (K) are designated with a number showing their position as, for instance (K4), indicating lysine as the 4th amino acid from the amino (N) end of the tail in the histone protein. Methylations {Me}, and acetylations [Ac] are common post-translational modifications on the lysines of the histone tails.
Some repression signals on a nucleosome.

Histone acetylation plays an important role in the regulation of gene expression. Hyperacetylated chromatin is transcriptionally active, and hypoacetylated chromatin is silent. A study on mice found that a specific subset of mouse genes (7%) was deregulated in the absence of HDAC1.[17] Their study also found a regulatory crosstalk between HDAC1 and HDAC2 and suggest a novel function for HDAC1 as a transcriptional coactivator. HDAC1 expression was found to be increased in the prefrontal cortex of schizophrenia subjects,[18] negatively correlating with the expression of GAD67 mRNA.

Non-histone effects

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It is a mistake to regard HDACs solely in the context of regulating gene transcription by modifying histones and chromatin structure, although that appears to be the predominant function. The function, activity, and stability of proteins can be controlled by post-translational modifications. Protein phosphorylation is perhaps the most widely studied and understood modification in which certain amino acid residues are phosphorylated by the action of protein kinases or dephosphorylated by the action of phosphatases. The acetylation of lysine residues is emerging as an analogous mechanism, in which non-histone proteins are acted on by acetylases and deacetylases.[19] It is in this context that HDACs are being found to interact with a variety of non-histone proteins—some of these are transcription factors and co-regulators, some are not. Note the following four examples:

  • HDAC6 is associated with aggresomes. Misfolded protein aggregates are tagged by ubiquitination and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome. HDAC 6 binds polyubiquitinated misfolded proteins and links to dynein motors, thereby allowing the misfolded protein cargo to be physically transported to chaperones and proteasomes for subsequent destruction.[20] HDAC6 is important regulator of HSP90 function and its inhibitor proposed to treat metabolic disorders.[21]
  • PTEN is an important phosphatase involved in cell signaling via phosphoinositols and the AKT/PI3 kinase pathway. PTEN is subject to complex regulatory control via phosphorylation, ubiquitination, oxidation and acetylation. Acetylation of PTEN by the histone acetyltransferase p300/CBP-associated factor (PCAF) can repress its activity; on the converse, deacetylation of PTEN by SIRT1 deacetylase and, by HDAC1, can stimulate its activity.[22][23]
  • APE1/Ref-1 (APEX1) is a multifunctional protein possessing both DNA repair activity (on abasic and single-strand break sites) and transcriptional regulatory activity associated with oxidative stress. APE1/Ref-1 is acetylated by PCAF; on the converse, it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its DNA repair activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormone gene.[24][25]
  • NF-κB is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via HDAC3 and HDAC6.[26]

These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs.

HDAC inhibitors

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Main article: Histone deacetylase inhibitor

Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example, valproic acid. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases.[27][28][29] Also in recent years, there has been an effort to develop HDIs for cancer therapy.[30][31] Vorinostat (SAHA) was FDA approved in 2006 for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) that have failed previous treatments. A second HDI, Istodax (romidepsin), was approved in 2009 for patients with CTCL. The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed.[32] In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.[33] HDIs are currently being investigated as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy.[34] Isoform selective HDIs which can aid in elucidating role of individual HDAC isoforms have been developed.[35][36][37][29]

HDAC inhibitors have effects on non-histone proteins that are related to acetylation. HDIs can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity. For the four examples given above (see Function) on HDACs acting on non-histone proteins, in each of those instances the HDAC inhibitor Trichostatin A (TSA) blocks the effect. HDIs have been shown to alter the activity of many transcription factors, including ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NFκB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, and YY1.[38][39]

The ketone body β-hydroxybutyrate has been shown in mice to increase gene expression of FOXO3a by histone deacetylase inhibition.[40]

Histone deacetylase inhibitors may modulate the latency of some viruses, resulting in reactivation.[41] This has been shown to occur, for instance, with a latent human herpesvirus-6 infection.

Histone deacetylase inhibitors have shown activity against certain Plasmodium species and stages which may indicate they have potential in malaria treatment. It has been shown that HDIs accumulate acetylated histone H3K9/H3K14, a downstream target of class I HDACs.[42]

See also

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References

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Histone deacetylase

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Histone deacetylases (HDACs) are a superfamily of enzymes that catalyze the removal of acetyl groups from the ε-amino groups of residues on both and non- proteins, thereby regulating and a wide array of cellular processes. In mammals, there are 18 distinct HDACs, phylogenetically classified into four main groups based on sequence similarity and catalytic mechanisms: Class I (HDAC1, HDAC2, HDAC3, and HDAC8), which are zinc-dependent and primarily nuclear; Class II, subdivided into IIa (HDAC4, HDAC5, HDAC7, HDAC9) and IIb (HDAC6, HDAC10), which shuttle between the nucleus and ; Class III (sirtuins SIRT1–SIRT7), which are NAD⁺-dependent; and Class IV (HDAC11), which shares features with both Class I and II. This reflects their diverse subcellular localizations and substrate specificities, enabling precise control over epigenetic and non-epigenetic modifications. The primary mechanism of HDACs involves deacetylating histones to promote chromatin condensation, which represses transcription by limiting access to DNA for transcriptional machinery. Beyond histones, HDACs target non-histone proteins such as transcription factors (e.g., p53), chaperones (e.g., HSP90), and cytoskeletal elements (e.g., tubulin), influencing pathways like cell proliferation, differentiation, apoptosis, and stress responses. For instance, Class IIa HDACs often function as signal-responsive scaffolds in multiprotein complexes, interacting with transcription factors like MEF2 to modulate tissue-specific gene programs during development. Dysregulation of these mechanisms can lead to altered protein acetylation patterns, contributing to pathological states across various tissues. HDACs play essential roles in physiological processes, including embryonic development, tissue homeostasis, and immune regulation, with specific isoforms implicated in , remodeling, and neuronal function. In disease contexts, aberrant HDAC activity is associated with cancers, neurodegenerative disorders, and dystrophies, where it promotes oncogenesis or impairs tissue repair. Therapeutically, HDAC inhibitors (HDACi), such as (approved by the FDA in 2006 for ), represent a class of targeted agents that induce hyperacetylation, leading to arrest, , and differentiation in malignant cells while sparing normal tissues. Emerging applications include pan-HDACi like givinostat (FDA-approved in 2024 for in patients aged 6 years and older), which has demonstrated improved muscle function and reduced in clinical trials.

Overview and Classification

Definition and superfamily

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from the ε-amino group of residues on proteins, primarily , resulting in condensation and transcriptional repression. This deacetylation activity counteracts the action of histone acetyltransferases (HATs), which add acetyl groups to promote an open structure and activation. The concept of histone acetylation as a regulatory modification was first proposed in 1964 by Vincent Allfrey and colleagues, who identified dynamic acetylation on histones in calf thymus nuclei and suggested its role in control. Enzymatic deacetylation of histones was subsequently demonstrated in 1969 by Akira Inoue and Daisaburo Fujimoto, who isolated an activity from calf thymus extracts capable of removing acetyl groups from acetylated histones. HDACs form a superfamily of 18 members in humans, divided into two major branches based on catalytic mechanisms and : the classical zinc-dependent HDACs (classes I, II, and IV) and the NAD⁺-dependent sirtuins (class III). The classical HDACs share a conserved catalytic domain of approximately 380 that coordinates a zinc ion essential for , while sirtuins possess a distinct catalytic core relying on NAD⁺ as a cofactor. This superfamily structure reflects evolutionary divergence, with classical HDACs forming a metalloenzyme group and sirtuins aligning with prokaryotic and eukaryotic deacetylases. The general reaction catalyzed by HDACs is a that reverses , represented as: Protein-Lys-NH-Ac+H2O→Protein-Lys-NH2+CH3COO−\text{Protein-Lys-NH-Ac} + \text{H}_2\text{O} \rightarrow \text{Protein-Lys-NH}_2 + \text{CH}_3\text{COO}^- This process yields free and without requiring , distinguishing it from the synthetic activity of HATs.

Classes and subtypes

Histone deacetylases (HDACs) in higher eukaryotes are classified into four classes based on their phylogenetic relationships to HDAC homologs and their dependence on specific cofactors for catalytic activity. Humans possess 18 HDACs in total, comprising 11 classical zinc-dependent enzymes across classes I, II, and IV, and 7 NAD+-dependent sirtuins in class III, with orthologs of these enzymes conserved across other eukaryotes. The classical HDACs (classes I, II, and IV) share approximately 30-40% sequence identity within their catalytic domains, reflecting their common evolutionary origin from Rpd3 and Hda1 proteins. Class I HDACs are zinc-dependent enzymes primarily localized in the nucleus and include the subtypes , HDAC2, HDAC3, and HDAC8. These enzymes exhibit high deacetylase activity toward histones and are integral components of multiprotein corepressor complexes, such as Sin3 and NuRD, which facilitate repression by recruiting HDACs to . For instance, and HDAC2 commonly associate with Sin3 and NuRD to modulate transcriptional silencing, while HDAC3 interacts with SMRT/NCoR complexes. Class II HDACs are also zinc-dependent but distinguished by their ability to shuttle between the nucleus and ; this class is subdivided into IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10). Subtypes in class IIa feature unique N-terminal extensions of approximately 600 residues that contain conserved motifs for protein-protein interactions, enabling their roles as signal-responsive scaffolds in pathways such as muscle differentiation and immune regulation through phosphorylation-mediated trafficking. In contrast, class IIb members like HDAC6 possess tandem catalytic domains and preferentially target non-histone substrates, with HDAC10 showing specificity for deacetylation. Class III HDACs, known as sirtuins, are NAD+-dependent and mechanistically distinct from the zinc-dependent classes; they include subtypes SIRT1 through SIRT7, with varied subcellular localizations. Among these, SIRT1 serves as a key regulator of by modulating pathways involved in , stress resistance, and genomic stability in response to caloric restriction and cellular levels. Class IV consists of a single member, HDAC11, which is zinc-dependent and exhibits a unique catalytic profile with both deacetylase and highly efficient acyl-hydrolase activity, particularly toward long-chain fatty acids on residues, outperforming its deacetylation function by over 10,000-fold. Recent studies have identified HDAC12 isoforms in non-mammalian eukaryotes, such as fish (e.g., ) and , arising from gene duplications of HDAC11, expanding the class IIb-like diversity in these organisms.

Evolutionary and Localization Aspects

Evolutionary history

Histone deacetylases (HDACs) trace their origins to an ancient protein superfamily present in prokaryotes, where HDAC-like enzymes functioned as deacylases for non-histone substrates. Bacterial homologs, including utilization proteins (AcuC) and acetylpolyamine amidohydrolases, exhibit structural and functional similarities to eukaryotic HDACs, indicating these prokaryotic enzymes as evolutionary precursors. Evidence from genomic analyses supports multiple events from to early eukaryotes, facilitating the integration of deacetylase activities into emerging systems. In eukaryotes, classical zinc-dependent HDACs emerged around 1.5 billion years ago in the Last Eukaryotic Common Ancestor (LECA), paralleling the of histone-based packaging. These enzymes, akin to the Rpd3 family (class I), enabled precise through histone deacetylation. Sirtuins (class III HDACs), however, predate this eukaryotic innovation, originating in and linked to NAD⁺-dependent in primordial cellular forms. Subsequent diversification occurred via gene duplications during metazoan , expanding HDAC repertoires to adapt to complex developmental needs. Class IIa HDACs (e.g., HDAC4, HDAC5, HDAC7, HDAC9) arose specifically in vertebrates following divergence from , allowing shuttling between cellular compartments for enhanced signaling integration. shows that budding yeast (Saccharomyces cerevisiae) harbor only five classical HDACs—three class I (Rpd3, Hos1, Hos2) and two class II (Hda1, Hos3)—with no class IIa members, whereas mammals possess 11 classical HDACs reflecting lineage-specific expansions. The catalytic domains remain highly conserved across eukaryotes, exhibiting over 60% sequence identity between human and yeast Rpd3, underscoring their fundamental role in deacetylation.

Subcellular distribution

Class I histone deacetylases (HDACs), including , HDAC2, HDAC3, and HDAC8, are predominantly localized in the nucleus of eukaryotic cells, where they associate closely with structures. For instance, and HDAC2 are frequently found enriched at promoter regions, facilitating their role in . Class II HDACs demonstrate dynamic nucleocytoplasmic shuttling, mediated by interactions with 14-3-3 proteins and phosphorylation-dependent signals that expose nuclear localization or export sequences. Among these, HDAC6 is primarily cytoplasmic and associates with as well as aggresomes, enabling non-nuclear functions. The class III HDACs, known as sirtuins, exhibit diverse subcellular distributions: SIRT1 localizes to both the nucleus and , SIRT2 is predominantly cytoplasmic, SIRT3, SIRT4, and SIRT5 are mainly mitochondrial, SIRT6 is primarily nuclear, and SIRT7 is primarily nucleolar/nuclear. Class IV HDAC11 is primarily nuclear but also displays cytoplasmic localization depending on cellular and tissue type. Subcellular localization of HDACs is commonly investigated using immunofluorescence microscopy, (GFP) fusion constructs for live-cell , and subcellular techniques, which have shown variations influenced by progression. Recent findings have revealed lysosomal localization of HDAC10, particularly in neuronal cells, highlighting its association with organelle-specific functions.

Mechanisms and Functions

Histone deacetylation mechanism

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from the ε-amino group of residues on histone tails, reversing to modulate structure. Classical HDACs (classes I, II, and IV) employ a zinc-dependent mechanism, while class III HDACs, known as sirtuins, utilize NAD⁺ as a cofactor. These mechanisms differ fundamentally in their catalytic strategies and structural requirements, enabling precise regulation of histone deacetylation within nucleosomes. In zinc-dependent HDACs, the catalytic core features a Zn²⁺ ion coordinated by conserved aspartate and residues, such as Asp178, His180, and Asp267 in HDAC8, which polarizes a bound to act as a . The substrate acetyl- enters a narrow hydrophobic tunnel leading to the , where Zn²⁺ also coordinates the carbonyl oxygen of the , enhancing its electrophilicity. The reaction proceeds via nucleophilic attack by the activated on the carbonyl carbon, forming a tetrahedral intermediate stabilized by Zn²⁺ and a general acid-base residue (e.g., His143 in HDAC8). Collapse of this intermediate expels the product, followed by deprotonation of the ε-amino group to yield free . This is represented by the equation: R-CO-NH-CH(R’)+H2O→R-COOH+H2N-CH(R’)\text{R-CO-NH-CH(R')} + \text{H}_2\text{O} \rightarrow \text{R-COOH} + \text{H}_2\text{N-CH(R')} where R denotes the and R' the protein . Crystal structures, such as that of human HDAC8 (PDB: 1T69), reveal the active site's architecture, including the substrate (~10 Å long) that accommodates the acetyl-lysine while excluding bulkier modifications. Kinetically, these enzymes exhibit Michaelis constants (Kₘ) of approximately 1–10 μM for acetylated substrates, reflecting efficient binding to tails; for instance, HDAC8 shows a Kₘ of ~4.5 μM for an acetyl-lysine . The product acts as a competitive inhibitor, with Kᵢ values in the millimolar range, potentially fine-tuning activity post-reaction. Sirtuins, in contrast, catalyze deacetylation through an NAD⁺-dependent pathway unique to class III HDACs. NAD⁺ binds first, followed by the acetyl-lysine substrate, which attacks the C1' carbon of NAD⁺, displacing and forming a metastable ADPR-peptidyl-imidate intermediate. of this imidate by releases deacetylated and generates the byproduct O-acetyl-ADP-ribose, linking deacetylation to cellular NAD⁺ levels. This mechanism ensures activity responds to metabolic states, with no Zn²⁺ involvement. Recent structural advances, including cryo-EM structures of HDAC complexes with nucleosomes, have illuminated context-dependent mechanisms. For classical HDACs, the 2024 cryo-EM structure of the Rpd3S complex (homologous to ) bound to reveals how the HDAC docks to the surface via accessory subunits, positioning the near tails for targeted deacetylation without disrupting DNA wrapping. Similarly, the 2023 cryo-EM structure of SIRT6 in complex with a (resolved at 2.7–3.1 Å) shows the prying apart DNA at the entry-exit site to access H3 K9 and K56, with an anchor stabilizing binding to the H2A/H2B acidic patch. These insights highlight allosteric adaptations enhancing substrate access within .

Non-histone protein effects

Histone deacetylases (HDACs) exert effects beyond by deacetylating , thereby modulating diverse cellular processes such as cytoskeletal organization, , and metabolic regulation. These enzymes target residues on non-histone substrates, altering their stability, localization, activity, or interactions with other molecules, often through mechanisms analogous to deacetylation but with broader substrate specificity due to cytoplasmic localization in some cases. For instance, class II HDACs like HDAC6 possess a catalytic core similar to nuclear HDACs but exhibit dual functionality, including ubiquitin-binding domains that facilitate deacetylation of misfolded proteins during stress responses. A prominent example is HDAC6-mediated deacetylation of α-tubulin at 40, which destabilizes and influences cytoskeletal dynamics essential for and intracellular transport. This modification reduces microtubule acetylation, promoting disassembly and affecting processes like and neuronal transport. Similarly, HDAC6 deacetylates the tumor suppressor at lysine 120, suppressing its transcriptional activity and thereby inhibiting induction. In metabolic contexts, class III HDAC () SIRT1 deacetylates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), enhancing its coactivator function to promote and oxidation in response to . HDAC6 also targets heat shock protein 90 (), disrupting its chaperone activity and leading to client protein degradation, which impacts protein stability and signaling pathways. This deacetylation facilitates HSP90's interaction with HDAC6's ubiquitin-binding domain, promoting of aggregated proteins. Regarding HDAC10, evidence suggests it contributes to deacetylation with low catalytic efficiency , potentially influencing dynamics in neurodegenerative contexts, though its primary substrates are polyamines like N-acetylspermidine. Class III sirtuins, including SIRT1, deacetylate forkhead box O (FOXO) transcription factors, such as FOXO1 and , enhancing their nuclear retention and transcriptional activation of genes involved in stress resistance and . Mass spectrometry-based has identified over 100 non-histone sites regulated by HDACs, with seminal studies mapping 388 lysine sites across 195 proteins, highlighting the widespread impact on cellular signaling. HDAC11 deacetylates proteins in cells, modulating transcriptional activity and protein stability in cancer contexts. These non-histone modifications underscore HDACs' role in integrating dynamics with broader cellular .

Regulation and Biological Roles

Regulatory mechanisms

Histone deacetylases (HDACs) are regulated at multiple levels, including post-translational modifications that modulate their activity, localization, and stability. of class IIa HDACs, such as HDAC4 and HDAC5, by kinases like CaMK and AMPK promotes their nuclear export through binding to 14-3-3 chaperone proteins, thereby controlling subcellular shuttling and transcriptional repression. For instance, CaMK HDAC4 at serines 246, 467, and 632, facilitating cytoplasmic retention, while AMPK targets HDAC5 at serines 259 and 498 to regulate metabolic . Other modifications, including SUMOylation and ubiquitination, influence HDAC stability; SUMOylation enhances the activity and protein interactions of class I HDACs like and HDAC2, whereas ubiquitination targets them for proteasomal degradation, fine-tuning their cellular abundance. HDAC function is further controlled through interactions with cofactors and corepressor complexes that dictate recruitment and enzymatic competence. Class I HDACs, such as , are recruited to via corepressors like mSin3 and NCoR, forming multiprotein complexes that mediate transcriptional silencing through targeted deacetylation. In contrast, class IIa HDACs (e.g., HDAC4, HDAC5) lack intrinsic deacetylase activity and depend on association with HDAC3 within NCoR/SMRT complexes for catalytic function, where the repression domain 3 (RD3) of NCoR directly binds these HDACs in an mSin3-independent manner. These interactions ensure context-specific regulation, with corepressors bridging HDACs to transcription factors. Transcriptional regulation of HDAC expression involves promoter elements and non-coding RNAs, leading to cell-type specific patterns. MicroRNAs, such as miR-449a, directly target the 3' untranslated region of HDAC1 mRNA, repressing its expression and thereby modulating cell growth and viability in contexts like . Similarly, the miR-449 family exhibits cell-type dependent downregulation, contributing to tissue-specific HDAC levels. Techniques like ChIP-seq have revealed promoter occupancy patterns, while kinase assays confirm phosphorylation events in regulatory cascades. Allosteric mechanisms and cofactor dependencies refine HDAC substrate specificity. Accessory domains in HDAC8, including a distal helix1-loop1-helix2 region, allosterically couple to the , influencing conformational states and recognition up to 28 Å away, as shown by NMR and simulations. For class III HDACs (sirtuins), NAD+ serves as an allosteric and cosubstrate; elevated NAD+ levels activate sirtuins like SIRT1 and SIRT3 by facilitating deacetylation, linking metabolic status to enzymatic output, whereas NAD+ depletion impairs their function. Recent studies highlight epigenetic feedback loops in HDAC autoregulation. The miR-449 family forms a circuit with and SIRT1, where HDAC/SIRT1 repression increases miR-449 expression, which in turn downregulates , enhancing chemosensitivity in models. Similarly, HDAC inhibition by induces de novo expression changes, upregulating (2.6-fold) and HDAC3 (2.1-fold) while downregulating HDAC7 (1.9-fold), suggesting autoregulatory loops that maintain HDAC homeostasis in response to pharmacological perturbations.

Roles in cellular processes

Histone deacetylases (HDACs) are integral to gene regulation, primarily by catalyzing the removal of acetyl groups from histones, which promotes chromatin condensation and represses transcription. This mechanism ensures precise control over gene expression patterns essential for cellular identity. For instance, HDAC1 and HDAC2 maintain pluripotency in embryonic stem cells by repressing differentiation-associated genes and sustaining the expression of core pluripotency factors like Oct4 and Nanog, thereby supporting self-renewal and preventing premature lineage commitment. In cell cycle progression and proliferation, HDACs modulate key checkpoints to coordinate DNA replication and division. HDAC3 facilitates the G1/S transition by deacetylating and stabilizing cyclin A, a critical regulator of S-phase entry and mitotic progression; consequently, HDAC3 inhibition disrupts these processes, leading to cell cycle arrest and reduced proliferative capacity. Class II HDACs further influence proliferation by interacting with non-histone targets, such as repressors of growth-promoting pathways. HDACs drive differentiation and development through targeted repression of lineage-specific transcription factors. Class II HDACs, including HDAC4 and HDAC5, bind to and inhibit myocyte enhancer factor 2 (MEF2), suppressing the activation of genes required for and limb development; this repression is relieved by signaling-induced nuclear export of these HDACs, allowing MEF2-dependent differentiation to proceed. Stress responses rely on HDAC-mediated deacetylation to activate repair and survival pathways. SIRT1 enhances DNA by deacetylating Ku70, promoting its recruitment to DNA double-strand breaks and accelerating lesion resolution. Similarly, SIRT1 deacetylates FOXO transcription factors under , boosting the expression of antioxidant genes like superoxide dismutase 2 to mitigate damage and promote cellular resilience. In metabolism, mitochondrial sirtuins fine-tune energy homeostasis. SIRT3 deacetylates and activates enzymes such as long-chain acyl-CoA dehydrogenase in the fatty acid oxidation pathway, enhancing β-oxidation efficiency during nutrient scarcity and preventing lipid accumulation. Recent investigations (as of 2024) have uncovered HDAC involvement in immune checkpoint regulation, where HDAC6 deacetylates STAT1 to promote its nuclear translocation and PD-L1 transcription, thereby modulating T-cell suppression in immune responses. Overall, HDACs operate in dynamic cycles with histone acetyltransferases (HATs), where opposing acetylation and deacetylation activities enable rapid, reversible modulation of states and protein functions to adapt to cellular demands.

Disease Associations and Therapeutics

Involvement in diseases

Histone deacetylases (HDACs) play a critical role in cancer through aberrant expression and activity, particularly in class I isoforms. Overexpression of has been observed in , where it contributes to activation by altering structure and patterns. Additionally, HDACs mediate epigenetic silencing of tumor suppressor genes, such as CDX1 and EPHB in colorectal tumors, by promoting histone deacetylation and condensation, thereby facilitating tumor progression. Class I HDACs, including , are frequently upregulated across various cancers, enhancing proliferative signaling and suppressing apoptotic pathways. In neurodegenerative disorders, dysregulation of specific HDACs exacerbates and neuronal damage. HDAC6 hyperactivity promotes accumulation in by inhibiting the chaperone activity of acetylated , leading to impaired clearance and formation. Elevated HDAC6 levels in affected neurons disrupt stability and exacerbate . Conversely, inhibition of SIRT2, a class III HDAC, has shown protective effects against neurodegeneration by reducing alpha-synuclein toxicity and ameliorating in models of Parkinson's and Huntington's diseases. Increased SIRT2 activity has been associated with exacerbated in models of these disorders. Cardiovascular diseases involve HDACs in maladaptive remodeling processes. HDAC4 and HDAC5, class IIa enzymes, repress MEF2 transcription factors in cardiomyocytes, thereby promoting pathological in response to stress signals. Their nuclear localization and interaction with MEF2 enhance fetal programs, contributing to cardiac enlargement and failure. Dysregulated HDAC4/5 activity is a key driver of hypertrophic responses in conditions like pressure overload. Inflammatory and autoimmune conditions feature HDAC-mediated enhancement of pro-inflammatory signaling. HDAC3 regulates cytokine production in rheumatoid arthritis synovial fibroblasts, where its activity sustains the expression of genes like IL-6 and TNF-α, perpetuating joint inflammation. Elevated HDAC3 levels in tissues correlate with increased inflammatory gene transcription programs. This dysregulation amplifies immune cell activation and tissue damage in autoimmune settings. Metabolic diseases, such as , are linked to reduced HDAC activity impairing insulin signaling. Downregulation of SIRT1 in insulin-resistant tissues decreases deacetylation of key substrates like PGC-1α, leading to diminished insulin sensitivity and glucose disruption. SIRT1 deficiency in adipose and hepatic cells exacerbates and beta-cell dysfunction. This pattern is evident in diabetic models where SIRT1 expression inversely correlates with disease severity. Genetic mutations in HDACs underlie certain congenital disorders. Loss-of-function mutations in HDAC8, identified in 2012, disrupt acetylation and complex stability, causing with features like and limb anomalies. These mutations impair HDAC8's deacetylase activity on SMC3, leading to cohesin dysfunction and developmental defects. Recent investigations highlight HDAC11's emerging role in fibrotic and post-infectious conditions. In 2025 studies, HDAC11 promotes renal fibrosis by inducing partial epithelial-mesenchymal transition and G2/M arrest in tubular cells, exacerbating deposition. HDAC11 also contributes to through deacetylation of 1, enhancing glycolytic shifts in fibroblasts. In the context of sequelae, HDAC11 modulates immune responses, with its dysregulation linked to persistent and fibrotic lung changes via altered profiles and T-cell function.

HDAC inhibitors and applications

Histone deacetylase inhibitors (HDACi) are classified into several chemical types, including hydroxamates such as vorinostat and belinostat, benzamides like entinostat, and cyclic peptides such as romidepsin. These inhibitors can be pan-HDACi, targeting multiple isoforms across classes I, II, and IV, or class-specific, such as tubacin, which selectively inhibits HDAC6. By 2025, the U.S. Food and Drug Administration (FDA) has approved five classical HDACi—vorinostat (2006, for cutaneous T-cell lymphoma), romidepsin (2009, for cutaneous and peripheral T-cell lymphomas), belinostat (2014, for peripheral T-cell lymphoma), panobinostat (2015, for multiple myeloma), and givinostat (2024, for Duchenne muscular dystrophy in patients aged 6 years and older)—with no approvals for sirtuin modulators to date. The primary mechanism of these inhibitors involves of the zinc ion in the HDAC , which traps the product and prevents substrate deacetylation, leading to hyperacetylation of histones and non-histone proteins. Isoform selectivity is achieved through structural modifications, such as capping groups that interact with unique surface features of specific HDAC classes, allowing targeted inhibition while minimizing off-target effects. In clinical applications, and belinostat are primarily used for hematologic malignancies like lymphomas, where they induce arrest and in cancer cells. Givinostat, a pan-HDACi, is approved for , demonstrating improved muscle function and reduced in clinical studies. Ongoing trials from 2023 to 2025 explore HDACi in solid tumors, including combinations with ; for instance, a phase II trial (NCT05268666) evaluates the LSD1/HDAC6 inhibitor JBI-802 in advanced solid tumors, showing enhanced immune responses. activators, such as analogs like SRT2104, have been investigated in early-phase trials for metabolic and inflammatory conditions but lack FDA approval for HDAC-related indications. Key challenges in HDACi therapy include toxicity from off-target effects, such as and gastrointestinal issues, which limit dosing, and acquired resistance through mechanisms like drug efflux pumps and HDAC mutations. Efforts to address these involve developing biomarkers, such as HDAC isoform expression levels or status, to guide patient selection and improve response rates. Recent advances include proteolysis-targeting chimeras (PROTACs) for degradative HDAC inhibition, with 2024 developments yielding selective degraders like TO-1187 for HDAC6, demonstrating superior antiproliferative activity and efficacy compared to traditional inhibitors. Additionally, HDACi are advancing in neurodegeneration, with phase II trials for exploring agents like RGFP966 to reduce and improve motor function.

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