Fact-checked by Grok 2 weeks ago

HDAC1

Histone deacetylase 1 (HDAC1) is a class I zinc-dependent enzyme that removes acetyl groups from the ε-amino groups of lysine residues on the N-terminal tails of core histones, promoting chromatin compaction and transcriptional repression by limiting access of transcriptional machinery to DNA.^[1] Encoded by the HDAC1 gene on human chromosome 1p35.2, it is ubiquitously expressed across tissues and primarily localized in the nucleus, where it functions as the catalytic core of multi-subunit repressor complexes such as Sin3, NuRD, CoREST, and MiDAC.^[2] Beyond histones, HDAC1 also deacetylates non-histone substrates like transcription factors (e.g., p53, E2F), and signaling proteins (e.g., AMPK), influencing diverse cellular processes including proliferation, differentiation, and apoptosis.^[1] HDAC1 plays critical roles in embryonic development and tissue homeostasis, with homozygous knockout mice exhibiting embryonic lethality before day 10.5 due to severe proliferation defects, growth retardation, and increased apoptosis.^[2] It exhibits functional redundancy with the closely related HDAC2 in most contexts, as combined deletion of both is required for pronounced phenotypes in tissues like the heart, skin, and immune cells, though HDAC1 has unique non-redundant functions in early embryogenesis, neuronal development, and skeletal formation.^[3] Dysregulation of HDAC1 activity is implicated in various pathologies, notably cancer—where it drives oncogenesis by repressing tumor suppressor genes—and neurological disorders, such as Huntington's disease, through aberrant non-histone deacetylation.^[1] As a therapeutic target, HDAC1 is inhibited by broad-spectrum histone deacetylase inhibitors (HDACi) like vorinostat (SAHA) and romidepsin, which are FDA-approved for treating cutaneous T-cell lymphoma by inducing hyperacetylation, cell cycle arrest, and apoptosis in cancer cells.^[1] Ongoing research focuses on HDAC1-selective inhibitors and activators to enhance efficacy and reduce off-target effects, with preclinical studies highlighting its potential in cardiovascular diseases, inflammation, and neurodegeneration.^[3]

Discovery and Nomenclature

Historical Background

The concept of histone deacetylation emerged in the late 1960s and early 1970s through biochemical experiments demonstrating the enzymatic removal of acetyl groups from histones. In 1970, Inoue and Fujimoto identified a histone deacetylase activity in extracts from calf thymus, where the enzyme catalyzed the release of acetate from radioactively labeled histones, establishing the existence of a specific deacetylase in mammalian tissues.^[4] This discovery built on earlier observations of histone acetylation by Allfrey et al. in 1964, shifting focus toward dynamic post-translational modifications in chromatin. During the 1980s and 1990s, research advanced the understanding of acetylation's regulatory role in chromatin structure and gene expression, linking hyperacetylation to open chromatin and gene activation, while deacetylation correlated with condensation and repression. Studies in yeast identified Rpd3 (reduced potassium dependence 3) as a key transcriptional repressor involved in these processes, with genetic screens revealing its necessity for silencing at promoters and telomeres. Rpd3's role in histone deacetylation was later confirmed, positioning it as a foundational homolog for eukaryotic HDACs and highlighting conserved mechanisms across species. In the mid-1990s, efforts to purify mammalian HDAC activity intensified, driven by the identification of transcriptional corepressors like Sin3 that mediated gene repression through deacetylation. Biochemical fractionation of HeLa cell nuclear extracts revealed HDAC activity tightly associated with the Sin3 complex, sensitive to inhibitors like trapoxin, which facilitated affinity purification.^[5] This work culminated in 1996 with the isolation of a mammalian HDAC as a direct homolog of yeast Rpd3, marking HDAC1's identification through sequence similarity and enzymatic assays that confirmed its deacetylase function in corepressor complexes.

Cloning and Initial Characterization

The human HDAC1 gene (ID: 3065) was cloned in 1996 through affinity purification using trapoxin, a cyclotetrapeptide inhibitor of histone deacetylation. Taunton et al. isolated two nuclear proteins exhibiting deacetylase activity from HeLa cell nuclear extracts bound to a trapoxin affinity matrix, followed by peptide microsequencing to identify matching expressed sequence tags (ESTs) in the human database. Full-length cDNA was subsequently obtained from a Jurkat T-cell library, revealing an open reading frame encoding a 488-amino-acid protein with strong sequence homology to the yeast transcriptional regulator Rpd3, suggesting conserved function in eukaryotic gene repression.^[5] Initial biochemical assays confirmed HDAC1 (initially termed HD1) as a catalytically active histone deacetylase. The recombinant protein hydrolyzed acetyl groups from core histones and synthetic acetyl-lysine substrates, including fluorogenic peptides mimicking histone tails, demonstrating specific deacetylase function independent of other cellular factors. This activity was potently inhibited by trichostatin A (TSA), a fungal metabolite known to block histone deacetylation in vivo, with an IC₅₀ of approximately 2 nM, linking HDAC1 to the mechanism of TSA-induced cell cycle arrest.^[5] Subcellular localization studies established HDAC1 as a nuclear enzyme. Immunofluorescence microscopy and fractionation experiments showed predominant enrichment in the nucleus of mammalian cells, aligning with its predicted role in chromatin remodeling at transcription sites. Early chromatin immunoprecipitation assays further indicated association with promoter regions, often in multiprotein complexes recruited by DNA-binding repressors.^[6] In nomenclature, HDAC1 was designated the founding member of class I histone deacetylases based on its compact structure, nuclear localization, and zinc-dependent catalytic mechanism, distinguishing it from subsequently identified class II enzymes like HDAC4, which feature larger sizes, cytoplasmic-nuclear shuttling, and additional regulatory domains.

Gene and Protein Structure

Genomic Organization

The human HDAC1 gene is located on the short arm of chromosome 1 at the cytogenetic band 1p35.3, spanning approximately 42 kilobases from position 32,291,921 to 32,333,635 on the forward strand (GRCh38.p14 assembly).^[7] It consists of 14 exons, with the majority encoding the functional protein domains, while intronic regions contribute to regulatory elements.^[8] The promoter region upstream of the HDAC1 transcription start site contains multiple Sp1 binding sites that facilitate recruitment of the HDAC1 protein itself, along with NF-Y, enabling autoregulation of expression.^[9] This promoter is responsive to cell cycle factors, such as E2F-responsive elements that modulate HDAC1 binding during G1 phase progression, ensuring tight control over proliferation-related transcription.^[10] The core promoter architecture, including these Sp1 sites, is highly conserved among mammals, reflecting its essential role in developmental and homeostatic gene regulation.^[9] Evolutionary conservation of HDAC1 is pronounced, with the coding sequence showing greater than 90% identity across vertebrate species, underscoring its fundamental role in chromatin modification. Orthologs are present in distant eukaryotes, including the Rpd3 protein in budding yeast (Saccharomyces cerevisiae) and fruit fly (Drosophila melanogaster), where they perform analogous functions in transcriptional repression.^[11] Alternative splicing of HDAC1 transcripts is infrequent, with the majority of variants retaining the full exon structure; however, rare isoforms arise from alternative 3' exon usage, resulting in proteins with modified C-terminal regions that may subtly alter stability or interactions.^[8] The canonical transcript, designated NM_004964.3, encodes the full-length 482-amino-acid protein and predominates in most tissues.^[7]

Protein Domains and Features

HDAC1 is a 482-amino-acid protein with a calculated molecular weight of approximately 55 kDa.^[12] The protein features a compact catalytic core flanked by N- and C-terminal extensions that contribute to its localization and regulatory properties. The N-terminal region includes motifs for homo-oligomerization, while the C-terminal extension, spanning beyond the catalytic domain, contains a lysine-rich nuclear localization signal (NLS) sequence KKAKRVKT (residues 438–444) essential for nuclear import.^[12]^[11] This NLS ensures predominant nuclear localization, though HDAC1 can shuttle under certain conditions.^[13] The central catalytic domain, encompassing approximately residues 59–428, adopts an α/β fold characteristic of class I histone deacetylases, forming a tubular active site tunnel approximately 11 Å in length that accommodates acetyl-lysine substrates.^[14] Within this domain, a conserved zinc-binding motif coordinates the catalytic Zn²⁺ ion via His141, His143, Asp99, and a water molecule hydrogen-bonded to Asp264, stabilizing the catalytic pocket and facilitating deacetylation.^[15] The domain's surface includes interfaces for dimerization, particularly with HDAC2, mediated by residues in the N-terminal and central regions that enable hetero- or homodimer formation to enhance stability and activity in complexes. Additionally, intrinsically disordered regions, notably in the C-terminal tail (beyond residue 431), provide flexibility for interactions with regulatory partners.^[16] Post-translational modifications, such as phosphorylation at Ser421 and Ser423 in the C-terminal region, modulate HDAC1's enzymatic activity and localization; these sites, targeted by kinases like CK2, increase deacetylase function when phosphorylated.^[17] Structural insights derive from X-ray crystallography of HDAC1 complexes, including PDB entry 4BKX (HDAC1 with MTA1 ELM2-SANT domains, 2.3 Å resolution) revealing how accessory domains encircle the catalytic core, and 5ICN (HDAC1:MTA1 with inhibitor, 1.8 Å) highlighting substrate tunnel details.^[18]^[19] The bacterial homolog structure (PDB 1C3S, 2.1 Å) informed early models of the conserved fold, while recent cryo-EM studies of HDAC1-containing complexes, such as the NuRD assembly (up to 3.1 Å resolution in 2023), depict full-length architecture in native contexts.^[20]^[21]

Enzymatic Mechanism

Catalytic Activity

HDAC1 catalyzes the Zn²⁺-dependent hydrolytic removal of acetyl groups from the ε-amino group of lysine residues on core histones, particularly H3 and H4, as well as non-histone proteins, yielding acetate and the deacetylated lysine residue.^[22] This deacetylation reaction is a key step in modulating chromatin structure and protein function. HDAC1 exhibits a strong preference for core histones over non-histone substrates such as tubulin, consistent with the general substrate selectivity of class I HDACs.^[11] The enzyme displays Michaelis-Menten kinetics with Km values for acetyl-lysine-containing peptides typically in the range of 1–10 μM, reflecting efficient binding to histone-derived substrates.^[23] HDAC1 activity is optimal at pH 7–8 and requires Zn²⁺ coordination in the active site for catalysis.^[24] It is potently inhibited by hydroxamate-class compounds, such as trichostatin A (TSA), with an IC₅₀ of approximately 2 nM.^[25] Beyond histones, HDAC1 demonstrates non-canonical deacetylation of non-histone targets, including the tumor suppressor p53 at specific lysine residues, which promotes p53 destabilization and ubiquitin-mediated degradation.^[26]

Structural Basis of Catalysis

The active site of HDAC1 features a narrow, tubular channel approximately 11 Å in depth, which accommodates the acetyl-lysine side chain of substrates. This channel is lined primarily by hydrophobic and aromatic residues, including Phe150 and Phe205, which form the narrowest constriction at about 7.5 Å and facilitate substrate positioning through van der Waals interactions. Additional residues such as His28, Pro29, Gly149, and Leu271 contribute to the channel's architecture, stabilizing the transition state via a hydrogen-bonding network.^[15] At the base of the channel lies the catalytic zinc ion (Zn²⁺), coordinated by Asp176, His178, and Asp264, which polarizes the substrate's carbonyl group and activates a bound water molecule for nucleophilic attack. The deacetylation mechanism proceeds in distinct steps: first, the acetyl-lysine enters the channel and binds, with its carbonyl oxygen coordinating to Zn²⁺ and forming a hydrogen bond with Tyr303 for precise orientation. Next, the Zn²⁺-His-Asp triad (involving His141 and Asp99) activates a water molecule by lowering its pKa, enabling nucleophilic attack on the carbonyl to form a tetrahedral intermediate stabilized by Zn²⁺ and surrounding residues. This intermediate then collapses, with His141 protonating the leaving amino group to release acetate and lysine products.^[27]^[15]^[28] Tyr303 plays a crucial role in substrate positioning by hydrogen-bonding to the acetyl group, ensuring alignment for efficient hydrolysis, while flexible loops at the channel entrance (e.g., residues 14–25 and 72–92) allow access and product egress. Mutations in channel residues like Phe150Ala reduce catalytic efficiency by up to 12-fold, primarily by impairing transition state stabilization rather than substrate binding.^[15]^[28] Inhibitors such as suberoylanilide hydroxamic acid (SAHA) bind within the active site by chelating the Zn²⁺ ion via their hydroxamate group, mimicking the tetrahedral intermediate and blocking the channel entrance. The inhibitor's linker is sandwiched between Phe150 and Phe205, preventing substrate access and halting catalysis.^[27]^[15]

Biological Roles

Transcriptional Regulation

HDAC1 functions as the catalytic subunit in several multi-protein co-repressor complexes, including Sin3, NuRD, CoREST, and MiDAC, which are recruited to target gene promoters by DNA-binding transcription factors. By deacetylating lysine residues on histone tails (primarily H3 and H4), HDAC1 promotes chromatin condensation, limiting access of RNA polymerase II and transcriptional activators to DNA, thereby repressing gene expression. This mechanism is crucial for silencing developmental genes, cell cycle regulators, and tumor suppressors in various cellular contexts. For instance, in response to differentiation signals, HDAC1-containing complexes repress pluripotency factors like Oct4 in embryonic stem cells to facilitate lineage commitment.^[1]^[2]

Involvement in Cellular Pathways

HDAC1 plays a pivotal role in regulating the cell cycle progression, particularly at the G1/S checkpoint, by deacetylating key proteins. Rb recruits HDAC1 to E2F-responsive promoters, where it deacetylates histones H3 and H4, promoting chromatin compaction and repression of genes required for S-phase entry, thereby enforcing G1 arrest. Similarly, HDAC1 deacetylates p53 at lysine residues such as K382, inhibiting p53 transcriptional activity and modulating the duration of p53-dependent cell cycle arrest and apoptosis in response to stress signals.^[29]^[30] These non-histone substrates underscore HDAC1's function beyond chromatin modification in maintaining cellular proliferation control. In the DNA damage response, HDAC1 is essential for coordinating the ATM kinase pathway, which senses double-strand breaks and initiates repair signaling. HDAC1 interacts with ATM to regulate its activation and downstream effectors, including phosphorylation of p53 and CHK2, thereby amplifying the checkpoint response to prevent aberrant cell cycle re-entry. Depletion of HDAC1 impairs ATM-dependent signaling, leading to defective DNA damage-induced G1/S arrest and increased genomic instability. This involvement highlights HDAC1's integration into kinase cascades for timely cellular responses to genotoxic stress. HDAC1 contributes to cellular differentiation and stem cell maintenance by repressing lineage-specific genes, ensuring proper embryonic development and self-renewal, with functional redundancy to HDAC2. In embryonic stem cells, HDAC1 maintains pluripotency by deacetylating histones at promoters of differentiation-associated genes, such as those involved in mesoderm or ectoderm lineages, thereby silencing them to prevent premature commitment. Conditional knockout of HDAC1 in mouse embryonic stem cells impairs proliferation and increases differentiation, though combined HDAC1/HDAC2 deletion severely disrupts self-renewal capacity. Homozygous HDAC1 knockout leads to embryonic lethality around E9.5-E10.5, with defects in proliferation and patterning due to failed maintenance of undifferentiated states in progenitor cells.^[31]^[3] In DNA repair mechanisms, HDAC1 modulates the acetylation status of repair factors like Ku70, a core component of the non-homologous end joining (NHEJ) pathway. By deacetylating Ku70 at lysine residues in its DNA-binding domain, HDAC1 promotes Ku70's association with DNA ends, facilitating efficient recruitment of the NHEJ machinery and ligation of double-strand breaks. Inhibition of HDAC1 increases Ku70 acetylation, impairing its chromatin tethering and reducing NHEJ efficiency, as observed in sensitized cells to ionizing radiation. This post-translational regulation positions HDAC1 as a critical modulator of repair fidelity, particularly in non-dividing cells reliant on NHEJ. HDAC1 influences cellular metabolism by deacetylating the transcriptional coactivator PGC-1α, which governs mitochondrial biogenesis and energy homeostasis. Deacetylation of PGC-1α by HDAC1 enhances its interaction with PPARγ and other nuclear receptors, promoting the expression of genes involved in oxidative phosphorylation and fatty acid oxidation. This regulation supports mitochondrial function under metabolic stress, such as nutrient deprivation, by optimizing energy production. Dysregulated HDAC1 activity alters PGC-1α acetylation, leading to impaired mitochondrial dynamics and reduced adaptive responses in energy-demanding tissues like liver and muscle.

Protein Interactions and Complexes

Major Co-repressor Complexes

HDAC1 serves as a core enzymatic subunit in several multi-subunit co-repressor complexes that mediate transcriptional repression through histone deacetylation. These complexes, including Sin3, NuRD, CoREST, and MiDAC, recruit HDAC1 to specific genomic loci to compact chromatin and silence gene expression, playing essential roles in development, differentiation, and cellular homeostasis.^[32]^[33] The Sin3 complex is one of the primary co-repressor assemblies containing HDAC1 and HDAC2, scaffolded by Sin3A or Sin3B along with associated proteins such as RbAp46, RbAp48, SAP18, SAP30, and the histone demethylase RBP2 (KDM5A). This complex targets promoters of repressed genes, facilitating deacetylation of histones H3 and H4 to enforce stable silencing, and is crucial for processes like Notch signaling regulation and mitochondrial gene control.^[32]^[34] Sin3A recruits HDAC1 via its conserved HDAC interaction domain (HID), enabling the complex to interact with sequence-specific repressors and modulate a broad repertoire of target genes during embryonic development.^[35] The NuRD (nucleosome remodeling and deacetylase) complex integrates HDAC1 and HDAC2 with ATP-dependent chromatin remodeling activity, featuring the helicase Mi2 (CHD3/CHD4), metastasis-associated proteins (MTA1/MTA2/MTA3), methyl-CpG-binding domain proteins (MBD2/MBD3), RbAp46/RbAp48, and p66 subunits. This coupling allows simultaneous histone deacetylation and nucleosome repositioning to repress transcription, particularly in developmental contexts such as maintaining embryonic stem cell pluripotency and suppressing genes like Snail in cancer progression.^[32]^[36] The complex's remodeling function, driven by Mi2's ATPase activity, enhances HDAC1's access to acetylated histones, promoting efficient chromatin condensation.^[37] The CoREST complex associates HDAC1 and HDAC2 with the scaffold protein CoREST (RCOR1), the lysine-specific demethylase LSD1 (KDM1A), and accessory factors like ZNF217 and p80, enabling coordinated deacetylation and H3K4 demethylation for gene repression. It plays a key role in silencing neuronal genes by binding RE1 elements via REST transcription factor, thereby restricting neuronal differentiation programs in non-neuronal cells and influencing hematopoietic and oncogenic processes.^[32]^[38] This complex's dual enzymatic activity ensures robust repression of neuron-specific loci during development.^[39] The MiDAC (microphthalmia-associated transcription factor deacetylase) complex contains HDAC1 and HDAC2 along with the scaffold protein MIDEAS and the DNA/nucleosome-binding protein DNTTIP1. It regulates cell cycle progression, particularly associating with cyclin A during mitosis, and is essential for embryonic development and neuronal differentiation by modulating neurodevelopmental gene expression programs.^[40]^[41] Assembly of these complexes relies on HDAC1's intrinsic dimerization, primarily mediated by its C-terminal domain, which forms homo- or heterodimers with HDAC2 to create a catalytically active core. Adaptor proteins such as Sin3, MTA, or CoREST then dynamically recruit this dimerized HDAC1/2 module, often stabilized by additional scaffolds like Sds3 in Sin3 or Mi2 in NuRD, allowing context-specific complex formation without direct HDAC1 interaction with DNA-binding repressors.^[42]^[35] This modular architecture ensures HDAC1's enzymatic activity is harnessed only within stable multi-protein units.00407-3.pdf)

Specific Interacting Partners

HDAC1 directly interacts with the tumor suppressor transcription factor p53, deacetylating it at lysine 382 (K382) to modulate its transcriptional activity and stability.^[43] This interaction has been validated through co-immunoprecipitation (co-IP) assays demonstrating physical association in cellular contexts.^[43] Similarly, HDAC1 binds to the retinoblastoma protein (Rb), enhancing Rb-mediated transcriptional repression of E2F target genes via recruitment to promoter regions; this partnership occurs through the C-terminal domain of HDAC1 and is confirmed by co-IP and complex purification studies.^[44]^[44] Among corepressors, HDAC1 forms a direct interaction with mSin3A, primarily through the HDAC-interaction domain (HID) of mSin3A, facilitating recruitment to chromatin for deacetylation.80214-7) Yeast two-hybrid screening and co-IP experiments have established this binding as essential for mSin3A's repressive function.80214-7) HDAC1 also associates with the nuclear receptor corepressor N-CoR, often bridged by mSin3A, to enable deacetylation in nuclear receptor-dependent repression; this interaction supports N-CoR's role in silencing gene expression and has been verified via co-IP in mammalian cells.^[45]^[45] Beyond transcription factors and corepressors, HDAC1 targets non-histone proteins as substrates. It deacetylates heat shock protein 90 (HSP90), regulating HSP90's chaperone activity and client protein stability, as evidenced by increased HSP90 acetylation upon HDAC1 knockdown in co-IP and acetylation assays. Although cortactin is primarily a substrate of HDAC6, HDAC1 indirectly influences cortactin-related pathways through shared complexes, but direct deacetylation remains unconfirmed. Protein interaction databases such as STRING identify approximately 50 high-confidence partners for HDAC1 (interaction score >0.7), including the above proteins, validated by methods like yeast two-hybrid and co-IP across multiple studies.^[46]

Regulation of HDAC1 Activity

Transcriptional Regulation

The HDAC1 gene is transcriptionally regulated by a GC-rich promoter lacking a TATA box, which contains multiple Sp1 binding sites and a CCAAT box recognized by the transcription factor NF-Y. These elements synergistically activate HDAC1 expression in a cell cycle-dependent manner, with Sp1 and NF-Y cooperating to drive promoter activity that is enhanced by growth factors and histone deacetylase inhibitors such as trichostatin A (TSA). The promoter also features binding sites for E2F transcription factors, contributing to the regulation of HDAC1 during cell cycle progression. This configuration ensures upregulation of HDAC1 during the S-phase, supporting proliferation in rapidly dividing cells.^[47]^[48] MicroRNAs miR-449a and miR-449b post-transcriptionally repress HDAC1 by binding to its 3' untranslated region, thereby reducing HDAC1 protein levels and inhibiting cell growth in cancer contexts such as prostate and lung tumors. This regulation provides a layer of control to limit HDAC1-mediated deacetylation in pathological proliferation.^[49]^[50]^[51] HDAC1 expression is elevated in proliferating cells, including those in embryonic tissues where it supports stem cell self-renewal and differentiation, and exhibits tissue-specific patterns with high levels in the brain and heart to facilitate neural and cardiac development. While HDAC1 itself contributes to the repression of various genes as part of co-repressor complexes, its own expression is primarily governed by these DNA and RNA-level mechanisms.^[52]^[53]^[54]^[3]

Post-Translational Modifications

HDAC1 undergoes several post-translational modifications that fine-tune its enzymatic activity, subcellular localization, and protein stability within co-repressor complexes. Phosphorylation, primarily mediated by casein kinase 2 (CK2), occurs at serine residues Ser421 and Ser423 in the C-terminal domain, enhancing HDAC1's deacetylase activity and facilitating its binding to core components of the Sin3 and NuRD complexes, such as Sin3A and RbAp48.^[55] This modification is constitutive in many cellular contexts but becomes dynamically regulated during the cell cycle, with elevated phosphorylation levels observed in mitosis to support chromatin remodeling and transcriptional silencing. Additionally, cyclin-dependent kinase 5 (CDK5) can phosphorylate HDAC1 at Ser421 in specific differentiation processes, such as osteoblast development, further linking this PTM to cellular proliferation control.^[12] Acetylation of HDAC1, catalyzed by histone acetyltransferases like p300/CBP, targets multiple lysine residues in its C-terminal region, including Lys432, Lys438, Lys439, and Lys441. This modification competitively inhibits HDAC1's deacetylase function by mimicking acetylated substrates and promotes its role in attenuating transcription, particularly in steroid receptor-mediated gene regulation where acetylated HDAC1 associates with glucocorticoid receptor complexes to dampen activity.^[56] HDAC1 exhibits auto-deacetylation capability at sites like Lys430, allowing self-regulation, though this process is inefficient in isolation and often requires integration into multiprotein complexes for optimal reversal of acetylation.^[57] Such dynamic acetylation-deacetylation cycles enable HDAC1 to balance repressive and permissive chromatin states. Sumoylation modifies HDAC1 at lysine residues, notably Lys444 and Lys476, through conjugation with SUMO1 or SUMO2/3, which stabilizes its incorporation into transcriptional repression complexes and amplifies gene silencing without directly altering intrinsic enzymatic activity.^[57] This PTM enhances HDAC1's interaction with partners like the Argonaute-guided silencing complex, contributing to heterochromatin maintenance.^[58] Desumoylation by sentrin/SUMO-specific proteases (SENPs), particularly SENP1, reverses this modification, thereby modulating complex stability and allowing HDAC1 to adapt to changing transcriptional demands.^[57] Ubiquitination targets HDAC1 for proteasomal degradation, primarily via K48-linked chains attached by E3 ligases such as Mdm2 and members of the TRIM family, including TRIM46, which promotes its turnover in response to cellular stress or oncogenic signals.^[57]^[59] This degradation pathway regulates HDAC1 protein abundance, with its half-life approximately 24 hours in many cellular contexts, though it can be reduced under specific stress conditions.^[60]

Pathological Implications

Role in Cancer

HDAC1 is frequently overexpressed in various solid tumors, including breast and colon cancers, where its elevated mRNA and protein levels have been documented through analyses of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets.^[61] This overexpression correlates with poor clinical outcomes, such as reduced distant metastasis-free survival and post-progression survival in breast cancer patients.^[61] Similarly, high HDAC1 expression is associated with unfavorable prognosis in lung and other solid malignancies, contributing to tumor progression and resistance mechanisms.^[62] In oncogenic contexts, HDAC1 exerts tumor-promoting effects by repressing key tumor suppressor genes, such as the cyclin-dependent kinase inhibitor p21^{WAF1/CIP1}, through direct recruitment to promoter regions and histone deacetylation, thereby facilitating uncontrolled cell proliferation.^[63] Additionally, HDAC1 drives epithelial-mesenchymal transition (EMT) by participating in repressive complexes that downregulate epithelial markers like E-cadherin and upregulate mesenchymal programs, as evidenced in hepatocellular carcinoma models where HDAC1 is essential for transforming growth factor-β1-induced EMT and cell migration.^[64] These mechanisms link HDAC1's enzymatic activity to enhanced invasiveness and metastatic potential in solid tumors. Genetic alterations in HDAC1 are relatively uncommon but include amplifications at its chromosomal locus 1p35.3, observed in subsets of cancers, and rare somatic mutations, particularly in the catalytic domain, which can disrupt complex assembly and gene regulation.^[65] Experimental studies demonstrate that HDAC1 knockdown significantly impairs tumor growth; for instance, in glioma xenografts, shRNA-mediated silencing reduced tumor volume in nude mice compared to controls, highlighting HDAC1's role in sustaining proliferation.^[66]

Associations with Other Diseases

HDAC1 has been implicated in neurodegenerative disorders, particularly Alzheimer's disease (AD) and Huntington's disease (HD). In AD, conflicting reports exist on HDAC1 expression, with some studies reporting elevated levels in the cerebral cortex of affected individuals compared to controls, contributing to altered gene expression profiles associated with synaptic dysfunction,^[67] while others indicate decreased levels in frontal cortex and hippocampus.^[68] This dysregulation is linked to tau pathology through transcriptional alterations affecting genes involved in tau processing and aggregation. Inhibition of HDACs has been shown to increase acetylated tau levels, which can promote tau aggregation by impairing its degradation.^[69] In HD, caused by polyglutamine (polyQ) expansion in the huntingtin protein, HDAC1 levels are increased, leading to reduced histone acetylation at gene loci involved in neuronal survival, exacerbating transcriptional dysregulation and neuronal degeneration.^[70] Selective inhibition of HDAC1 ameliorates polyQ-induced phenotypes in cellular and animal models of HD, highlighting its pathological role.^[71] In cardiac pathologies, HDAC1 is upregulated in models of heart failure and contributes to pathological remodeling. During cardiac hypertrophy, elevated HDAC1 represses the expression of anti-hypertrophic genes, such as those involved in fetal gene program suppression, thereby promoting maladaptive growth and fibrosis.^[72] This mechanism is evident in pressure-overload models, where class I HDACs like HDAC1 mediate signal-responsive repression of protective transcriptional programs, ultimately leading to ventricular dysfunction.^[73] Recent investigations also indicate that HDAC1 suppresses key cardiac genes like cardiac troponin I (cTnI) with aging, further linking its dysregulation to heart failure progression.^[74] HDAC1 plays a critical role in inflammatory responses underlying autoimmune diseases, notably rheumatoid arthritis (RA). In RA synovial tissues, HDAC1 expression and nuclear activity are significantly elevated compared to osteoarthritis, correlating with increased production of pro-inflammatory cytokines.^[75] HDAC1 modulates NF-κB signaling by deacetylating the p65 subunit, enhancing its transcriptional activity and promoting inflammation in synovial fibroblasts, which drives joint destruction.^[76] This pathway is upregulated by TNFα, amplifying HDAC1's contribution to chronic inflammation in RA.^[77] Recent findings as of 2025 have extended HDAC1's associations to viral infections, including persistent SARS-CoV-2 effects. In chronic viral infections, HDAC1 regulates the formation of intermediate-exhausted CD8+ T cells, influencing immune exhaustion and viral persistence through chromatin-mediated gene silencing.^[78] For COVID-19, inhibition of class I HDACs including HDAC1 has been shown to enhance SARS-CoV-2 replication in lung epithelial and mesothelial cells by altering chromatin accessibility, suggesting its role in restricting viral latency-like states via repressive epigenetic modifications.^[79] These insights position HDAC1 as a modulator of antiviral immunity and potential target for managing post-acute sequelae.^[80]

Therapeutic Targeting

HDAC Inhibitors Targeting HDAC1

Histone deacetylase inhibitors (HDACis) targeting HDAC1 are classified based on their selectivity profiles, with pan-HDAC inhibitors affecting multiple isoforms including HDAC1 through broad enzymatic blockade. Vorinostat (SAHA), approved by the FDA in 2006, exemplifies this class as a hydroxamic acid-based compound that chelates the catalytic Zn²⁺ ion in the HDAC active site, thereby inhibiting deacetylation activity across class I and II HDACs.^[27] It exhibits potent inhibition of HDAC1 with an IC₅₀ of approximately 10 nM, leading to hyperacetylation of histones and non-histone proteins.^[81] Class I selective HDACis prioritize HDAC1, HDAC2, and HDAC3 while minimizing effects on class II isoforms, offering improved therapeutic windows by reducing off-target toxicities. Entinostat (MS-275), a benzamide derivative, demonstrates preference for these class I enzymes, with an IC₅₀ of about 300 nM against HDAC1 and weaker activity against HDAC8 (IC₅₀ > 10 μM).^[82] Its design incorporates an aromatic cap and linker that interacts with the HDAC1 surface groove, facilitating selective binding near the Zn²⁺-chelating moiety without broad class II engagement.^[83] Isoform-specific approaches, including proteolysis-targeting chimeras (PROTACs), enable targeted degradation of HDAC1 alongside inhibition, enhancing efficacy by removing the enzyme from cellular complexes. For instance, cereblon-recruiting PROTACs such as compound 7, featuring a 12-carbon alkyl linker attached to a class I HDAC warhead, achieve selective HDAC1 degradation (DC₅₀ ~0.1–1 μM) over HDAC3 with minimal impact on other isoforms, leveraging ubiquitin-proteasome pathways for dual functional disruption.^[84] These degraders, reported in recent studies around 2023–2024, outperform traditional inhibitors by sustaining HDAC1 suppression even in resistant cellular contexts.^[85] Development trends as of 2025 emphasize next-generation HDAC1-targeted agents with enhanced isoform selectivity to mitigate class II off-target effects, incorporating advanced structural motifs like optimized linkers and non-hydroxamic zinc binders for better pharmacokinetics and reduced toxicity.^[86] This shift draws on high-resolution crystal structures of HDAC1 to refine pocket-specific interactions, prioritizing compounds that spare HDAC6 and HDAC10 while amplifying HDAC1 blockade.^[87]

Clinical Applications and Developments

Vorinostat, a non-selective HDAC inhibitor that targets HDAC1 among others, received FDA approval in 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease following at least two systemic therapies.^[88] Similarly, romidepsin, another HDAC inhibitor with activity against HDAC1, was approved by the FDA in 2009 for relapsed or refractory CTCL and expanded in 2011 to include peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.^[89] These approvals marked the initial clinical validation of HDAC1 inhibition as a therapeutic strategy in hematologic malignancies, with response rates of approximately 30% observed in pivotal trials for both agents.^[90] Ongoing clinical trials continue to explore HDAC1-targeted inhibitors in solid tumors, particularly breast cancer. In the phase III E2112 trial (NCT02115282), entinostat, a class I-selective HDAC inhibitor including HDAC1, combined with exemestane was evaluated in hormone receptor-positive, HER2-negative advanced breast cancer; while it did not meet the primary progression-free survival (PFS) endpoint (median PFS 3.7 months vs. 3.3 months, HR 0.87, p=0.055), subgroup analyses suggested potential benefits in patients with specific biomarkers.^[91] Earlier phase II data from ENCORE 301 showed entinostat plus exemestane improved median PFS to 4.3 months compared to 2.3 months with exemestane alone (HR 0.73), representing approximately a 27% reduction in progression risk. Combinations with PD-1 inhibitors are also under investigation; for instance, in a phase I/II trial (NCT02453620), entinostat with nivolumab and ipilimumab in advanced solid tumors, including breast cancer, yielded objective response rates of 10% in hormone receptor-positive and 40% in triple-negative subtypes as reported in 2024.^[92] These efforts aim to enhance immunotherapy efficacy by modulating the tumor microenvironment through HDAC1 inhibition.^[93] Emerging research focuses on selective HDAC1 inhibitors for non-oncologic applications, such as neurodegeneration. CI-994, a class I HDAC inhibitor targeting HDAC1 and HDAC2, has demonstrated preclinical neuroprotection in models of Alzheimer's disease by increasing histone acetylation, reducing neuroinflammation, and improving cognitive function; 2025 studies highlight potential for crossing the blood-brain barrier with minimal off-target effects.^[94] Phase I trials for such selective agents in neurodegenerative disorders are anticipated, building on CI-994's established safety profile from prior oncology studies.^[95] Clinical development of HDAC1-targeted inhibitors faces challenges, including toxicity profiles such as thrombocytopenia, reported in up to 30% of patients across trials and often requiring dose adjustments or discontinuation.^[96] Additionally, biomarkers like HDAC1 expression levels in tumors are being explored for patient selection to optimize response rates and minimize adverse events, with higher expression correlating to improved outcomes in some HDAC inhibitor studies.^[86]

References

[1]
A short guide to histone deacetylases including recent progress on ...
Feb 19, 2020 · In this review, current knowledge of HDACs is briefly described with an emphasis on recent progress in research on HDACs, especially on class IIa HDACs.
[2]
The many roles of histone deacetylases in development and ...
Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes.The Hdac Superfamily · Class Iia Hdacs · Hdac2
[3]
The physiological roles of histone deacetylase (HDAC) 1 and 2
May 23, 2013 · HDAC1/2 activity has been implicated in the development of numerous tissue and cell types, including heart, skin, brain, B-cells and T-cells.
[4]
Histone Deacetylase From Calf Thymus - PubMed
Histone Deacetylase From Calf Thymus. Biochim Biophys Acta. 1970 Nov 11;220(2):307-16. doi: 10.1016/0005-2744(70)90015-x. Authors. A Inoue, D Fujimoto. PMID ...Missing: early discovery
[5]
A mammalian histone deacetylase related to the yeast ... - PubMed
Both proteins were identified by peptide microsequencing, and a complementary DNA encoding the histone deacetylase catalytic subunit (HD1) was cloned from a ...Missing: HDAC1 | Show results with:HDAC1
[6]
Homo-oligomerisation and nuclear localisation of mouse histone ...
Apr 20, 2001 · A lysine-rich sequence within the carboxy terminus of HDAC1 is crucial for nuclear localisation of the enzyme. We identify a C-terminal nuclear ...Missing: Taunton 1996 size 488
[7]
3065 - Gene ResultHDAC1 histone deacetylase 1 [ (human)] - NCBI
Sep 14, 2025 · Genomic analysis reveals HDAC1 regulates clinically relevant transcriptional programs in Pancreatic cancer. BCL11B and the NuRD complex ...Missing: exons | Show results with:exons
[8]
Gene: HDAC1 (ENSG00000116478) - Summary - Homo_sapiens
Chromosome 1: 32,291,921-32,333,635 forward strand. ... This gene has 21 transcripts (splice variants), 276 orthologues and 10 paralogues. Transcripts. Show ...
[9]
Autoregulation of Mouse Histone Deacetylase 1 Expression - PubMed
Tight control of HDAC1 expression is essential for development and normal cell cycle progression. In this report, we analyzed the regulation of the mouse HDAC1 ...Missing: conservation | Show results with:conservation<|separator|>
[10]
Cell cycle-dependent recruitment of HDAC-1 correlates with ...
Our data show that a histone deacetylase, HDAC-1, is stably bound to an E2F target promoter during early G1 in proliferating cells and released at the G1–S ...
[11]
Histone Deacetylases (HDACs): Evolution, Specificity, Role in ...
The first discovery of HDACs dates back the early 1970s, when scientists identified enzymes able to remove acetate from acetate labeled histone solutions in ...
[12]
HDAC1 - Histone deacetylase 1 - Homo sapiens (Human) | UniProtKB
Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4)Missing: exons span
[13]
HDAC1 nuclear export induced by pathological conditions is ... - NIH
Aug 1, 2010 · We report here that cytosolic HDAC1 is detected in damaged axons in brains of human patients with Multiple Sclerosis and of mice with cuprizone-induced ...
[14]
The Histone Deacetylase Family: Structural Features and ... - MDPI
These domains feature critical catalytic sites, such as zinc ions and arginine residues, essential for their enzymatic activity [33]. In contrast, the HDAC C- ...The Histone Deacetylase... · 1.2. Hdac Structure And... · 2. Hdac Inhibitors<|separator|>
[15]
Residues in the 11 Å Channel of Histone Deacetylase 1 Promote ...
Histone deacetylase 1 (HDAC1) has been linked to cell growth and cell cycle regulation, which makes it a widely recognized target for anticancer drugs.
[16]
Exclusion of HDAC1/2 complexes by oncogenic nuclear condensates
Apr 27, 2024 · To this end, we focused on HDAC1, which has N-terminal histone deacetylase and C-terminal disordered region (Supplementary Fig. 8a). By deletion ...
[17]
Histone deacetylase 1 phosphorylation promotes enzymatic activity ...
Dec 14, 2001 · Human HDAC1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, Ser(421) and Ser(423), were unambiguously identified.
[18]
4BKX: The structure of HDAC1 in complex with the dimeric ELM2 ...
Jul 3, 2013 · Here we report the structure of HDAC1 in complex with MTA1 from the NuRD complex. The ELM2-SANT domains from MTA1 wrap completely around HDAC1.
[19]
5ICN: HDAC1:MTA1 in complex with inositol-6-phosphate and a ...
May 11, 2016 · The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate ...
[20]
1C3S: CRYSTAL STRUCTURE OF AN HDAC ... - RCSB PDB
Sep 15, 1999 · Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic ...
[21]
Class I histone deacetylase complex: Structure and functional ...
A solution structure (PDB entry: 2LD7) of a binary complex of SAP30, a subunit of the mammalian Rpd3L/Sin3A histone deacetylase complex, with PAH3 of Sin3A ...
[22]
Erasers of Histone Acetylation: The Histone Deacetylase Enzymes
### Summary of HDAC1 Catalytic Activity (Class I HDACs)
[23]
Histone deacetylase 1 (HDAC1) assay | BMG LABTECH
The resulting KM value was determined to be 58.89 μM. Subsequent to the KM evaluation the assay was performed in presence of a known HDAC1 inhibitor (SAHA).
[24]
Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants ...
The kinetic rate constants of HDAC inhibitors differentially affect histone acetylation, cell viability, and gene expression.
[25]
Trichostatin A Is a Histone Deacetylase Inhibitor with Potent ...
The purpose of this study was to evaluate the antiproliferative and HDAC inhibitory activity of TSA in vitro in human breast cancer cell lines and to assess its ...
[26]
Deacetylation of p53 modulates its effect on cell growth and apoptosis
Nov 16, 2000 · Here we show that the deacetylation of p53 is mediated by an histone deacetylase-1 (HDAC1)-containing complex. We have also purified a p53 ...
[27]
Structure, Mechanism, and Inhibition of the Zinc-Dependent Histone ...
Zinc-dependent histone deacetylases (HDACs) regulate proteins by hydrolyzing acetyllysine, acting as 'erasers' in cellular processes. They are also known as ...
[28]
Distinct Biochemical Properties of the Class I Histone Deacetylase ...
Histone H3 peptide (S10-K18) was re-constructed from the existing peptide inhibitor-bound HDAC1 crystal structure (PDB 5ICN) using ChimeraX and Rosetta.
[29]
Autoregulation of Mouse Histone Deacetylase 1 Expression - PMC
In this report, we analyzed the regulation of the mouse HDAC1 gene by deacetylases and acetyltransferases. The murine HDAC1 promoter lacks a TATA box consensus ...
[30]
https://pmc.ncbi.nlm.nih.gov/articles/PMC137207/
[31]
HDAC1 and HDAC2 integrate the expression of p53 mutants in ...
Mar 30, 2017 · We show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine ...
[32]
Regulation of p53 tumour suppressor target gene expression by the ...
Sep 21, 2006 · Regulation of p53 tumour suppressor target gene expression by the p52 NF‐κB subunit ... (B) Analysis of p53, HDAC1 and p300 recruitment to ...
[33]
miR-449a targets HDAC-1 and induces growth arrest in prostate ...
Apr 9, 2009 · Further, our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer ...Missing: 449b | Show results with:449b
[34]
miR-449a targets HDAC-1 and induces growth arrest in prostate ...
Mar 2, 2009 · Our data indicate that miR-449a regulates cell growth and viability in part by repressing the expression of HDAC-1 in prostate cancer cells.Missing: HDAC1 | Show results with:HDAC1
[35]
Combining microRNA-449a/b with a HDAC inhibitor has a ...
These results suggest that miR-449a/b may have a tumor suppressor function and might be a potential therapeutic candidate in patients with primary lung cancer.
[36]
HDAC1 Regulates Neuronal Differentiation - PMC
During embryonic development, HDAC1 and HDAC2 are highly expressed in neuroepithelial cells and neural stem cells (NSCs), and their expression pattern overlaps ...
[37]
HDAC1 regulates pluripotency and lineage specific transcriptional ...
Abstract. Epigenetic regulation of gene expression is important in maintaining self-renewal of embryonic stem (ES) and trophoblast stem (TS) cells. Histone.Hdac1 Regulates Pluripotency... · Hdac1 Occupies Core... · Hdac1 Binding Is Associated...
[38]
The role of histone deacetylases in embryonic development
Dec 19, 2022 · Thus, HDAC1/2 played an essential role in maintaining cellular proliferation and self renewal of stem cells by upholding the expression of ...
[39]
Physiological Roles of Class I HDAC Complex and Histone ...
Sep 7, 2010 · In this paper, we summarize the distinct and cooperative roles of four class I HDAC complexes, Sin3, NuRD, CoREST, and NCoR/SMRT, with respect ...
[40]
https://www.nature.com/articles/s41467-020-17078-8
[41]
Sin3: Master Scaffold and Transcriptional Corepressor - PMC
Identification of core Sin3/HDAC complex components. Further biochemical purification and characterization of the Sin3 complex revealed that, in addition to ...
[42]
Structural insights into the assembly of the histone deacetylase ...
In the process, we uncover some unexpected similarities and differences with the mechanism of HDAC1/2 recruitment in the NuRD corepressor complex; we also show ...
[43]
The structure of the core NuRD repression complex provides ... - eLife
Apr 21, 2016 · The NuRD complex is a multi-protein transcriptional corepressor that couples histone deacetylase and ATP-dependent chromatin remodelling activities.
[44]
Analysis of the NuRD subunits reveals a histone deacetylase core ...
Interestingly, the NuRD complex also possesses nucleosome remodeling activity, most likely because of the presence of Mi2, a member of the SWI2/SNF2 helicase/ ...
[45]
More than a Corepressor: The Role of CoREST Proteins in ... - eNeuro
Feb 19, 2020 · CoREST-mediated gene repression. CoREST forms a complex with HDAC1/2 and LSD1 to elicit transcriptional repression. A, CoREST binds to DNA ...
[46]
the role of the HDAC/CoREST/LSD1/REST repressor complex
In neurons destined to harbor latent virus (checkpoint 3), HSV hijacks the same repressor complex to silence itself as a first step in the establishment of the ...
[47]
SPRR2A enhances p53 deacetylation through HDAC1 and down ...
Jun 25, 2012 · SPRR2A enhances p53 deacetylation through HDAC1 and down regulates p21 promoter activity.<|separator|>
[48]
DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses ...
Here we show that the predominant mammalian DNA methyltransferase, DNMT1, co-purifies with the retinoblastoma (Rb) tumour suppressor gene product, E2F1, and ...Missing: interaction | Show results with:interaction
[49]
Nuclear receptor repression mediated by a complex ... - PubMed
May 2, 1997 · In addition, we demonstrate that the recently characterized histone deacetylase 1 (HDAC1) interacts with Sin3A and SMRT to form a multisubunit ...
[50]
None
Nothing is retrieved...<|control11|><|separator|>
[51]
Regulation of histone deacetylase activities and functions by ... - NIH
Several studies have found that phosphorylation dynamics can regulate HDAC interactions, functions, and localization during mitosis. One study demonstrated that ...
[52]
HDAC1 Acetylation Is Linked to Progressive Modulation of Steroid ...
Jun 9, 2006 · HDAC1 in repressed chromatin is highly acetylated, while the deacetylase found on transcriptionally active chromatin manifests a low level of ...
[53]
The Post-Translational Code of Class I HDAC1 and HDAC2 - PMC
HDAC11 is the only member identified so far belonging to class IV; it is a zinc-dependent deacetylase sharing common features with both class I and class II ...
[54]
HDAC1 SUMOylation promotes Argonaute-directed transcriptional ...
May 18, 2021 · Our findings suggest how SUMOylation of HDAC1 promotes the recruitment and assembly of an Argonaute-guided chromatin remodeling complex that ...Missing: K468 | Show results with:K468
[55]
SNP rs4971059 predisposes to breast carcinogenesis and ...
Aug 30, 2021 · Consistently, knockdown of TRIM46 increased the half‐life of HDAC1 (Fig 3H). These observations suggest that TRIM46 targets HDAC1 for ...
[56]
HDAC1: a promising target for cancer treatment - NIH
Oct 31, 2024 · Bar: 50 µm. HDAC1, histone deacetylase 1; Ca, cancer; LUAD, lung ... Meanwhile, the examination of KM plotter revealed contrasting outcomes.
[57]
The expression of histone deacetylase HDAC1 correlates with ... - NIH
In addition, HDAC1 overexpression is often associated with poor prognosis in breast and lung cancer [3, 4]. Moreover, HDAC1 silencing by siRNA results in ...Missing: TCGA | Show results with:TCGA
[58]
The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target ... - NIH
HDAC1 was identified as one of the members of the HDAC family that negatively regulate p21 expression in human tumor cells (27). ... Indeed, a tumor suppressor ...
[59]
Histone deacetylase 1 is required for transforming growth factor-β1 ...
HDAC1 is required for TGF-β1-induced EMT and cell migration in hepatocytes. HDAC1 downregulates ZO-1 and E-cadherin, and its high expression is linked to HCC ...
[60]
Mutations on the surface of HDAC1 reveal molecular determinants ...
Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation.Missing: amplification 1p35.
[61]
Knockdown of HDAC1 expression suppresses invasion and induces ...
These results indicate that HDAC1 knockdown inhibits growth of tumor xenograft in nude mouse. Figure 6. Knockdown of HDAC1 in glioma cells reduces tumor growth ...
[62]
Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the ...
Elevated levels of acetylated tau have been observed in AD patients [19,30], and acetylated tau has been colocalized with insoluble tau aggregates in the brain ...Missing: HDAC1 | Show results with:HDAC1
[63]
Role of histone deacetylases and their inhibitors in neurological ...
2. The role of HDAC in Huntington disease. The increase in HDAC1 and HDAC5 protein levels leads to decreased acetylation of related gene loci ...
[64]
The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in ...
Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease.
[65]
Inhibition of class I histone deacetylase with an apicidin derivative ...
For example, whereas class II HDACs suppress pro-hypertrophic genes, class I HDACs might repress expression of anti-hypertrophic genes. If the anti-hypertrophic ...2.1 In Vitro Histone... · 2.2 Histone Deacetylase... · 3. Results
[66]
Control of Cardiac Growth by Histone Acetylation/Deacetylation
Jan 6, 2006 · Accordingly, inhibition of these HDACs could result in derepression of such antihypertrophic genes and a consequent block to hypertrophy. (2) ...Abstract · Histone Deacetylases · Class Ii Hdacs Act As...
[67]
Unlocking cardiac health: exploring the role of class I HDACs in ...
Jul 14, 2025 · Aberrant HDAC activity has been implicated in various pathological processes underlying CVD, including inflammation, endothelial dysfunction, hypertrophy, ...
[68]
Increased activity and expression of histone deacetylase 1 in ...
Jul 7, 2010 · Our results showed nuclear HDAC activity and expression of HDAC1 were significantly higher in RA than in OA synovial tissues, and they were upregulated by TNFα ...
[69]
Histone deacetylase 1 regulates tissue destruction in rheumatoid ...
Jul 7, 2015 · In this study, we have investigated the role of histone deacetylase (HDAC) enzymes in RA synovial fibroblasts (RASFs), a key cellular mediator ...Histone Deacetylase 1... · High Hdac1 Expression In... · Hdac1 Regulates Pathways...<|separator|>
[70]
Epi-revolution in rheumatology: the potential of histone deacetylase ...
May 7, 2024 · Recent studies suggest that HDACi could offer a viable therapeutic strategy for RA, with potential mechanisms including the inhibition of synovial tissue ...
[71]
Hdac1 as an early determinant of intermediate-exhausted CD8 + T ...
Using chronic viral infection, we show that histone deacetylase 1 (Hdac1) was specifically required for the formation of antigen-specific T EX -int cells.Missing: COVID- latency silencing 2024
[72]
HDAC1-3 inhibition increases SARS-CoV-2 replication and ... - NIH
Aim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).Missing: latency 2024 2025
[73]
New target identified for the development of specific immunotherapies
Jun 10, 2025 · A research team led by the Medical University of Vienna has discovered a previously unknown role for the epigenetic regulator HDAC1 in chronic viral infections.
[74]
SAHA (Vorinostat), HDAC inhibitor (CAS 149647-78-9) | Abcam
$$65 delivery 7-day returnsPotent non-selective HDAC inhibitor (IC50 values are 10 and 20 nM for HDAC1 and HDAC3, respectively). Induces apoptosis and shows antiproliferative effects ...
[75]
Entinostat (MS-275) | HDAC inhibitors/activators ... - Selleck Chemicals
Rating 5.0 (418) Entinostat (MS-275, SNDX-275) strongly inhibits HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM in cell-free assays, compared with HDACs 4, 6, 8, and 10.Missing: piperazine | Show results with:piperazine
[76]
Entinostat is a histone deacetylase inhibitor selective for class 1 ...
Entinostat is a histone deacetylase inhibitor selective for class 1 histone deacetylases and activates HIV production from latently infected primary T cells.Missing: piperazine | Show results with:piperazine
[77]
Cereblon-recruiting proteolysis targeting chimeras (PROTACs) can ...
Nov 5, 2024 · Cereblon-recruiting proteolysis targeting chimeras (PROTACs) can determine the selective degradation of HDAC1 over HDAC3†.
[78]
Optimization of Class I Histone Deacetylase PROTACs Reveals that ...
We demonstrate that HDAC1/2 degradation by PROTACs correlates with enhanced global gene expression and apoptosis, important for the development of more ...
[79]
Targeting histone deacetylase 1: Inhibition and activation as ...
This review provides a comprehensive overview of HDAC1-selective ligands, including inhibitors and activators, published primarily between 2018 and early 2025, ...
[80]
Overview of class I HDAC modulators: Inhibitors and degraders
Oct 5, 2024 · This review provides a comprehensive overview of class I HDAC enzymes and inhibitors, by initially introducing their structure and biological roles.
[81]
[PDF] Approval Letter(s) - accessdata.fda.gov
Oct 6, 2006 · This new drug application provides for the use of Zolinza (vorinostat) Capsules for the treatment of cutaneous manifestations in patients with ...
[82]
[PDF] nda 022393/s-004 accelerated approval - accessdata.fda.gov
Jun 16, 2011 · ... 2011, to the FDA TC of. May 16, 2011, you agree to continue to follow patients enrolled in the front-line trial of. CHOP +/- romidepsin in ...
[83]
[PDF] NDA Review - accessdata.fda.gov
Aug 10, 2006 · This new drug application seeks approval of vorinostat for the treatment of patients with cutaneous T-cell lymphoma (CTCL) who have progressive, ...
[84]
Study Details | NCT02115282 | ClinicalTrials.gov - ClinicalTrials.gov
Endocrine therapy using exemestane may fight breast cancer by lowering the amount of estrogen the body makes. Entinostat may stop the growth of tumor cells by ...
[85]
Entinostat, nivolumab and ipilimumab for women with advanced ...
Feb 14, 2024 · We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, ...
[86]
Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic ...
Jan 13, 2023 · Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma.Missing: HDAC1 neurodegeneration analogs
[87]
Therapeutic effects of class I HDAC inhibitor CI‐994 in Alzheimer's ...
CI‐994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI‐994 can cross ...Missing: selective analogs
[88]
Dose Effects of Histone Deacetylase Inhibitor Tacedinaline (CI-994 ...
Our results suggest CI-994 can reduce HAL-induced motor and memory side effects in aged mice. These effects may act through an increase of acetylation at the ...Missing: HDAC1 analogs
[89]
Thrombocytopenia induced by the histone deacetylase inhibitor ...
Jul 25, 2013 · A thrombocytopenia is observed in up to 30% of the patients and can be either isolated or associated with other cytopenias.