Affinage

HDAC4

Histone deacetylase 4 · UniProt P56524

Length
1084 aa
Mass
119.0 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HDAC4 is a class IIa histone deacetylase that functions as a signal-responsive repressor of transcription and a regulator of non-histone protein acetylation, integrating extracellular cues to control muscle differentiation, skeletal development, neuronal survival, and immune and metabolic programmes (PMID:11504882, PMID:30843886, PMID:31618641). Its activity is governed primarily by nucleocytoplasmic shuttling: phosphorylation at 14-3-3-binding sites by CaMKII, SIK kinases, PKA, GSK3β, and CDKL5 retains HDAC4 in the cytoplasm, while dephosphorylation by PP2A (and counter-regulation among PKA and CaMKII pathways) permits nuclear import, where HDAC4 represses MEF2- and Runx2-dependent transcription (PMID:11504882, PMID:18045992, PMID:27466189, PMID:33590335, PMID:33148508). In the nucleus HDAC4 silences differentiation and target genes via MEF2 and Runx2, and assembles into corepressor complexes—with HDAC1/HDAC2 to erase H2BK120 acetylation and license BRCA1/CtIP-dependent homologous recombination (PMID:38874468), and with HDAC5/DREAM to repress NCX3 (PMID:31696766). HDAC4 stability is set by a layered degradation programme involving SIK/GSK3β-primed and Smurf2-mediated ubiquitination, K559 sumoylation, and caspase-3 cleavage at Asp289 (PMID:21118993, PMID:24934156, PMID:25475100, PMID:25447540). Beyond chromatin, cytoplasmic HDAC4 directly deacetylates a broad set of non-histone substrates—including MEKK2, FoxO3, HIF1α, myosin heavy chain, PGC-1α, Hsc70, GSDMD, glutaminase, and RUNX2—thereby controlling MAPK/AP1-driven muscle atrophy, autophagy, hypoxic metabolism, pyroptosis, and protein turnover (PMID:22658415, PMID:29529137, PMID:31618641, PMID:35864951, PMID:38326336, PMID:38057370). HDAC4 also restrains innate immunity by binding TBK1/IKKε to block IRF3 phosphorylation (PMID:29800227) and activates Th17 Il17a/f transcription via JunB (PMID:38657041), and contributes to neurodegeneration through polyglutamine-length-dependent cytoplasmic co-aggregation with mutant huntingtin (PMID:24302884). Missense HDAC4 mutations that impair FoxO1 deacetylation in pancreatic β-cells cause diabetes (PMID:30968599).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2001 High

    Established HDAC4 as a signal-controlled MEF2 repressor whose nuclear access—and thus suppression of the myogenic programme—is gated by phosphorylation-dependent 14-3-3 binding downstream of CaMKIV.

    Evidence Overexpression, live-cell localization, CaMKIV activation, 14-3-3 co-IP, and MEF2 reporter assays

    PMID:11504882

    Open questions at the time
    • Did not identify the phosphatase that reverses the modification
    • Endogenous physiological trigger of CaMKIV activity not defined
  2. 2007 High

    Identified PP2A as the phosphatase that opposes 14-3-3 retention, dephosphorylating Ser298 to license HDAC4 nuclear import, defining the on/off logic of shuttling.

    Evidence In vitro/in vivo binding, okadaic acid, PP2A siRNA, and Ser298 mutagenesis

    PMID:18045992

    Open questions at the time
    • Which upstream signals direct PP2A to HDAC4 not resolved
    • Holoenzyme specificity in different tissues unaddressed
  3. 2008 High

    Extended HDAC4 repression beyond MEF2 to Sp1-dependent promoters (p21) and to cardiac sarcomere biology via deacetylation of the Z-disc protein MLP, showing both chromatin and structural-protein substrates.

    Evidence ChIP, co-IP, siRNA in glioblastoma; immunohistochemistry, EM, and MLP-knockout mice in cardiac muscle

    PMID:18250163 PMID:18850004

    Open questions at the time
    • Generality of Sp1 recruitment across cell types unclear
    • Direct catalytic dependence on MLP not fully separated from complex effects
  4. 2008 High

    Revealed a catalytic-independent, NLS-region-dependent neuroprotective and CDK1-inhibitory function, showing HDAC4 can act without its deacetylase domain.

    Evidence Forced neuronal expression, HDAC inhibitor negative control, CDK1 activity assays, and HDAC4 knockout mouse cerebellar analysis

    PMID:18498087

    Open questions at the time
    • Molecular mechanism linking the NLS region to CDK1 inhibition unknown
    • Direct binding partners mediating protection not identified
  5. 2010 High

    Defined a degradation arm of HDAC4 regulation, showing GSK3β phosphorylation of Ser298 (primed by Ser302) within PEST1 triggers ubiquitin-proteasomal turnover linked to KLF2 and motility.

    Evidence In vitro GSK3β kinase assay, GSK3β siRNA, S298/S302 mutagenesis, and ubiquitination assays

    PMID:21118993

    Open questions at the time
    • E3 ligase for this event not identified here
    • Interplay between Ser298 in import (PP2A) versus degradation (GSK3β) not reconciled
  6. 2012 High

    Demonstrated that HDAC4 can act as a transcriptional ACTIVATOR by deacetylating and activating MEKK2 to drive MAP kinase/AP1-dependent atrophy genes, decoupling a function from its canonical repressor role.

    Evidence HDAC4-MEKK2 co-IP, deacetylation assays, AP1-inactivation epistasis, and denervation mouse model; CaMKIIδ2-HDAC4/5 phosphorylation in VSMCs

    PMID:22360269 PMID:22658415

    Open questions at the time
    • Switch between repressor and MEKK2-activator modes not mechanistically defined
    • Substrate selectivity rules among non-histone targets unknown
  7. 2012 Medium

    Linked HDAC4 to cancer regulatory networks as a miR-155 target and BCL6 corepressor partner controlling lymphoma cell proliferation and survival.

    Evidence Luciferase miRNA target validation and ectopic expression/rescue in DLBCL cells

    PMID:23169640

    Open questions at the time
    • BCL6-HDAC4 complex composition not detailed
    • Direct genomic targets of the corepressor complex not mapped
  8. 2013 High

    Identified HDAC4 as a polyglutamine-length-dependent huntingtin interactor whose reduction rescues synaptic dysfunction in HD without affecting global transcription, placing a cytoplasmic, transcription-independent role at the center of HD pathology.

    Evidence Co-IP, genetic HDAC4 reduction in HD mouse models, and synaptic/behavioral readouts; parallel AcetylScan proteomics showing no global deacetylase role in postnatal brain

    PMID:24278330 PMID:24302884

    Open questions at the time
    • Direct deacetylation substrate(s) relevant to HD not defined
    • Mechanism by which HDAC4 modulates aggregate kinetics unresolved
  9. 2013 Medium

    Broadened cytoplasmic sequestration functions, showing HDAC4 retains ATF4 in the cytoplasm to blunt ER-stress (CHOP/TRB3) apoptosis.

    Evidence HDAC4-ATF4 co-IP, fractionation, and transcriptional reporter assays

    PMID:24308964

    Open questions at the time
    • Single Co-IP context; reciprocal validation limited
    • Catalytic requirement for ATF4 retention not established
  10. 2014 High

    Established HDAC4 as a node integrating PTH/sympathetic cues in bone, where Smurf2-mediated degradation or ATF4 association tunes MEF2c-driven Rankl and osteoclast differentiation; chondrocyte studies linked p38/caspase-3 cleavage at Asp289 to Runx2 de-repression and hypertrophy.

    Evidence Ubiquitination assays, multiple co-IPs, Rankl reporter, and genetic mouse models; caspase-3 cleavage and D289 mutagenesis with MKK6 transgenic mice

    PMID:24934156 PMID:25447540

    Open questions at the time
    • Quantitative balance between degradation and nuclear retention under physiological signaling unclear
    • Tissue-specific E3 ligase repertoire incomplete
  11. 2014 High

    Defined a muscle-stem-cell role, showing HDAC4 supports Pax7-dependent satellite cell proliferation, restricts adipogenesis, and regulates targets including Lix1, P21, and Sharp1.

    Evidence Conditional HDAC4 KO in satellite cells, RNA-seq, and rescue experiments

    PMID:25205686 PMID:29472596

    Open questions at the time
    • Direct versus indirect regulation of identified targets not fully separated
    • Catalytic dependence of satellite cell phenotypes unclear
  12. 2015 High

    Expanded the kinase regulatory network to SIK2/PKA in adipocytes and tied HDAC4 to GLUT4-dependent glucose uptake, and established HDAC4 as an injury-responsive transcriptional regulator in sensory neurons driving thermal hypersensitivity.

    Evidence SIK2-HDAC4-PP2A co-IP, S358A mutant, glucose uptake assays; conditional sensory-neuron KO with Calca/Trpv1 qPCR and CFA pain model

    PMID:25472719 PMID:25903105

    Open questions at the time
    • Direct substrate underlying glucose-uptake effect not identified
    • Whether sensory transcriptional effects are MEF2-dependent unaddressed
  13. 2015 Medium

    Showed sumoylation at K559 couples to ubiquitin-dependent degradation controlling cardiomyocyte vulnerability, and demonstrated a catalytic-independent N-terminal domain sufficient for photoreceptor neuroprotection.

    Evidence K559R sumoylation mutant, ubiquitination/MG132 assays in cardiomyocytes; transgenic N-terminal domain expression in rd1 mice

    PMID:25475100 PMID:26272629

    Open questions at the time
    • SUMO E3 ligase and its trigger not identified
    • Molecular basis of catalytic-independent neuroprotection unresolved
  14. 2016 High

    Identified CDKL5 as a direct HDAC4 kinase enforcing cytoplasmic retention in neural precursors, mechanistically linking HDAC4 mislocalization to impaired neuronal maturation.

    Evidence In vitro CDKL5 kinase assay, Cdkl5 KO mouse, ChIP, MEF2A binding, and pharmacological rescue

    PMID:27466189

    Open questions at the time
    • CDKL5 target residues on HDAC4 not pinpointed here
    • Whether SIRT1-stabilizing role intersects neuronal phenotypes unknown
  15. 2016 Low

    Linked HDAC4 to senescence control via SIRT1 stabilization, with knockdown causing premature senescence.

    Evidence Overexpression/knockdown in fibroblasts with sumoylation and protein-stability assays

    PMID:26414199

    Open questions at the time
    • Single sumoylation assay without rigorous mechanistic follow-up
    • Direct enzymatic link between HDAC4 and SIRT1 sumoylation not established
  16. 2017 Medium

    Defined a non-transcriptional immune-suppressive function: HDAC4 binds TBK1/IKKε kinase domains to block IRF3 phosphorylation and IFN-β induction within a negative feedback loop.

    Evidence HDAC4-TBK1/IKKε co-IP, IRF3 phospho and translocation assays, and IFN-β reporter

    PMID:29800227

    Open questions at the time
    • Whether kinase inhibition requires deacetylase activity unclear
    • In vivo relevance to antiviral defense not tested here
  17. 2018 Medium

    Established HDAC4 as a direct deacetylase of FoxO3a in endothelium that activates autophagy and Ang II-driven vascular inflammation.

    Evidence siRNA knockdown, FoxO3a co-depletion, autophagy inhibitor, and Ang II models with LC3-II readout

    PMID:29529137

    Open questions at the time
    • Direct deacetylation of FoxO3a not shown in vitro in this study
    • Acetyl-lysine sites not mapped
  18. 2019 High

    Catalogued direct skeletal-muscle non-histone substrates (myosin heavy chain, PGC-1α, Hsc70) and connected HDAC4 deacetylation to denervation-induced atrophy and MuRF1 ubiquitination.

    Evidence In vitro deacetylation assays, class IIa-selective inhibitors, PGC-1α co-IP, and denervation mouse model

    PMID:31618641

    Open questions at the time
    • Site-specific deacetylation residues incompletely defined
    • Relative contribution of each substrate to atrophy not partitioned
  19. 2019 Medium

    Defined an HDAC4/HDAC5/DREAM corepressor complex repressing NCX3 and an HD-specific endogenous Hdac4 interactome enriched in vesicular trafficking/synaptic functions, including the WASH complex.

    Evidence Co-IP, ChIP, and stroke model for DREAM; affinity-purification MS across HD mouse series with WASH co-IP validation

    PMID:31040226 PMID:31696766

    Open questions at the time
    • Functional consequence of WASH-HDAC4 interaction not defined
    • Whether NCX3 repression requires HDAC4 catalytic activity unclear
  20. 2019 Medium

    Provided human disease genetics linking HDAC4 missense mutations to impaired β-cell FoxO1 deacetylation and diabetes, and showed HDAC4 controls SP1/KLF5-dependent MKK7 transcription in glioma.

    Evidence Exome/Sanger sequencing with mutant-construct insulin/FoxO1 assays; ChIP, co-IP, deacetylation, and xenograft for the SP1/KLF5/MKK7 axis

    PMID:30963560 PMID:30968599

    Open questions at the time
    • Causality of HDAC4 variants requires broader cohort/functional confirmation
    • Determinants of activator-versus-repressor switching on SP1/KLF5 not defined
  21. 2020 High

    Resolved the competition between PKA (nuclear retention via S265/266) and CaMKII (export) in cardiomyocytes and showed redox modification (Nox4/H2O2 cysteine oxidation, Ser632) disrupts the HDAC4/MEF2A complex.

    Evidence Live imaging with phosphomutants across species and pharmacology; Nox4/H2O2 system with redox-insensitive mutant and tube-formation assay

    PMID:32818796 PMID:33590335

    Open questions at the time
    • Integration of redox and phospho-inputs on a single HDAC4 pool unresolved
    • Disease-stage-specific dominance mechanisms incompletely defined
  22. 2020 High

    Mapped the PTHrP→cAMP/PKA→SIK→HDAC4 cascade controlling chondrocyte hypertrophy with HDAC5 redundancy, completing the kinase-to-Runx2 axis in skeletal development.

    Evidence Multiple SIK and HDAC4/5 mouse genetic models with phosphorylation and growth-plate phenotyping

    PMID:30843886 PMID:33148508

    Open questions at the time
    • Quantitative thresholds determining HDAC4 versus HDAC5 dominance unclear
    • Direct SIK phosphosites on HDAC4 in this context not enumerated
  23. 2022 High

    Expanded the non-histone substrate repertoire to deacetylation events that control ubiquitination of target proteins—glutaminase K311 (anti-TRIM21), LHPP K6 (pro-TRIM21 degradation), and GSDMD K248 (anti-pyroptosis)—establishing deacetylation-coupled ubiquitin regulation as a recurrent HDAC4 mechanism.

    Evidence In vitro deacetylation assays, substrate-TRIM21 co-IPs, site mutagenesis, ubiquitination and pyroptosis readouts

    PMID:35864951 PMID:37023940 PMID:38326336

    Open questions at the time
    • How phosphorylation gates HDAC4 catalysis on these substrates only partly defined (GSDMD via PP1)
    • Tissue specificity of these substrate choices unaddressed
  24. 2022 High

    Defined deacetylase-independent mRNA-stabilizing functions, with cytoplasmic HDAC4 stabilizing Trim72 mRNA for membrane repair in dystrophic muscle, and showed ALKBH5-driven m6A demethylation stabilizes Hdac4 mRNA upstream of FoxO3-driven atrophy.

    Evidence Conditional KO in mdx mice with Trim72/cytoplasmic-HDAC4 rescue; m6A-seq, HDAC4-FoxO3 co-IP, and Alkbh5 muscle KO

    PMID:35142084 PMID:35170869

    Open questions at the time
    • Mechanism by which HDAC4 stabilizes Trim72 mRNA unknown
    • Whether mRNA-binding is direct unresolved
  25. 2022 Medium

    Connected HDAC4 to inflammatory regulation via HMGB1 deacetylation (limiting nuclear export and sepsis-associated inflammation) under SP1 transcriptional control.

    Evidence ChIP of SP1 at HDAC4 promoter, HDAC4-HMGB1 co-IP, and gain/loss-of-function in septic mice

    PMID:35780770

    Open questions at the time
    • Direct deacetylation sites on HMGB1 not mapped
    • In vivo dependence on catalytic activity not isolated
  26. 2023 High

    Placed HDAC4 in a chromatin-repair complex with HDAC1/HDAC2 that erases H2BK120ac to enable BRCA1/CtIP recruitment and homologous recombination, with HDAC4 loss driving DNA damage and senescence.

    Evidence Complex co-IP, ChIP of BRCA1/CtIP/γH2AX, H2BK120ac analysis, and RAS-induced senescence model

    PMID:38874468

    Open questions at the time
    • Whether HDAC4 directly deacetylates H2BK120 or scaffolds HDAC1/2 unresolved
    • Recruitment signal to damage sites unknown
  27. 2023 Medium

    Defined SIK3 as an HDAC4 kinase regulating shuttling in hippocampal neurons and showed HDAC4 deacetylates RUNX2 to promote its degradation, linking HDAC4 to synaptic plasticity gene expression.

    Evidence SIK3-HDAC4 co-IP, ChIP-qPCR, viral gene transfer, electrophysiology, and AD mouse behavioral assays

    PMID:38057370

    Open questions at the time
    • SIK3 phosphosites on HDAC4 not enumerated
    • Causal contribution to AD phenotypes incompletely established
  28. 2024 High

    Established a Th17-activating function in which HDAC4 partners with JunB to transactivate Il17a/f, with therapeutic relevance in colitis, and a circRNA/NUDT4-driven nuclear-translocation axis directing RUNX2 degradation to suppress pancreatic cancer growth.

    Evidence HDAC4-JunB co-IP, conditional KO, and colitis model; RNA pulldown, HDAC4-RUNX2 co-IP, and luciferase assays in pancreatic cancer

    PMID:38297362 PMID:38657041

    Open questions at the time
    • Whether HDAC4 deacetylase activity is required for Il17a/f activation unclear
    • Generality of NUDT4-mediated dephosphorylation beyond pancreatic cancer untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single shuttling-controlled enzyme selects among its many histone and non-histone substrates, and what determines its switch between repressor, transcriptional activator, and catalytic-independent (mRNA-stabilizing, scaffolding) modes in a given cell, remains unresolved.
  • No unifying model of substrate selectivity
  • Quantitative integration of competing phospho/redox/sumoylation inputs lacking
  • Structural basis for catalytic-independent functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0140110 transcription regulator activity 5 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 4 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-397014 Muscle contraction 2 R-HSA-73894 DNA Repair 1
Partners
FOXO3HDAC5JUNBMEF2MEKK2PP2ARUNX2TBK1
Complex memberships
HDAC4/HDAC1/HDAC2 (H2BK120ac eraser)HDAC4/HDAC5/DREAMPP2A holoenzyme complex (with HDAC4)

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 HDAC4 interacts specifically with the MEF2 transcription factor and represses its activity; HDAC4 nuclear localization suppresses the myogenic programme and MEF2-dependent transcription. Activation of CaMKIV prevents HDAC4 nuclear entry by promoting its binding to 14-3-3 proteins in a phosphorylation-dependent manner, thereby relieving inhibition of muscle differentiation. Overexpression, live-cell localization assays, constitutively active CaMKIV, 14-3-3 co-immunoprecipitation, MEF2 transcriptional reporter assays Nucleic acids research High 11504882
2007 HDAC4 forms a complex with PP2A holoenzyme (Cα, Aα, B/PR55α subunits); the N-terminus of HDAC4 interacts with the catalytic subunit of PP2A. PP2A dephosphorylates HDAC4 and controls its nuclear import. Serine 298 is a key phosphorylation site that, when phosphorylated, blocks nuclear import; its dephosphorylation by PP2A is required for nuclear entry. In vitro and in vivo binding studies, okadaic acid inhibition, siRNA knockdown of PP2A, site-directed mutagenesis of Ser298 Molecular biology of the cell High 18045992
2008 HDAC4 interacts with the Sp1 transcription factor, binds the Sp1/Sp3-binding-site-rich p21(WAF1/Cip1) proximal promoter, and reduces histone H3 acetylation at that promoter, thereby repressing p21 expression through a p53-independent, Sp1-dependent mechanism. siRNA knockdown, ChIP, co-immunoprecipitation, in vitro glioblastoma model Oncogene Medium 18850004
2008 HDAC4 associates with cardiac sarcomeres, specifically at the Z-disc and I- and A-bands. HDAC4 deacetylates the Z-disc protein MLP (muscle LIM protein); HDAC inhibition (including antibody against HDAC4) increases myofilament calcium sensitivity in a MLP-dependent manner, establishing that HDAC4 regulates myofilament contractile activity via MLP acetylation. Immunohistochemistry, electron microscopy, co-immunoprecipitation, HDAC inhibitor treatment, MLP knockout mice The Journal of biological chemistry High 18250163
2008 HDAC4 protects neurons from apoptosis and inhibits cell-cycle progression; the protective action is nuclear and mediated by a region containing the nuclear localization signal but does not require the catalytic HDAC domain. HDAC4 inhibits CDK1 activity; HDAC4 knockout mice show elevated CDK1 activity and progressive loss of cerebellar Purkinje neurons. Forced expression in neurons, chemical HDAC inhibitors (negative result for neuroprotection), CDK1 activity assay, HDAC4 knockout mouse analysis, BrdU incorporation Developmental neurobiology High 18498087
2010 HDAC4 ubiquitin-dependent degradation is regulated by GSK3β-mediated phosphorylation of Ser298 within the PEST1 sequence; serum starvation triggers GSK3β-dependent poly-ubiquitination and proteasomal degradation of HDAC4. Phosphorylation of Ser302 serves as priming phosphorylation. HDAC4 degradation is linked to regulation of KLF2 transcription and cell motility. In vitro kinase assay (GSK3β phosphorylating HDAC4), siRNA knockdown of GSK3β, site-directed mutagenesis (S298, S302), ubiquitination assays Molecular biology of the cell High 21118993
2011 HDAC4 regulates HIF1α protein acetylation and stability: HDAC4 shRNA increases HIF1α acetylation while HDAC4 overexpression decreases it. Acetylation of the first five lysine residues (K10, K11, K12, K19, K21) in HIF1α N-terminus renders the protein resistant to HDAC4- and HDACi-mediated inhibition. HDAC4 inhibition decreases HIF-1 transcriptional activity, hypoxia target gene expression, glycolysis, and docetaxel resistance. Stable shRNA knockdown, HDAC4 overexpression, site-directed mutagenesis of HIF1α lysines, HIF-1 transcriptional reporter, metabolic assays The Journal of biological chemistry High 21917920
2012 HDAC4 activates AP1-dependent transcription in denervated muscle independently of its canonical transcriptional repressor activity. HDAC4 binds and promotes deacetylation and activation of MEKK2 (a MAP3K), thereby stimulating the MAP kinase cascade and AP1-dependent atrophy gene expression. AP1 inactivation recapitulates HDAC4 deficiency and blunts neurogenic muscle atrophy. Co-immunoprecipitation of HDAC4-MEKK2 complex, deacetylation assay, genetic epistasis with AP1 inactivation, denervation mouse model Molecular cell High 22658415
2012 miR-155 directly targets HDAC4 mRNA, reducing HDAC4 protein levels in B cells. HDAC4 functions as a corepressor partner of BCL6; ectopic HDAC4 expression in DLBCL cells reduces miR-155-induced proliferation and clonogenic potential and increases apoptosis. miRNA target validation (luciferase reporter), ectopic expression assays, proliferation and apoptosis readouts Proceedings of the National Academy of Sciences of the United States of America Medium 23169640
2013 HDAC4 associates with huntingtin (Htt) in a polyglutamine-length-dependent manner and co-localizes with cytoplasmic inclusions. HDAC4 reduction delayed cytoplasmic aggregate formation, restored BDNF transcript levels, and rescued neuronal and cortico-striatal synaptic function in HD mouse models, without affecting global transcription or nuclear Htt aggregation. Co-immunoprecipitation (HDAC4-Htt interaction), genetic HDAC4 reduction in HD mouse models, synaptic function assays, behavioral phenotyping PLoS biology High 24302884
2013 HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo: absence of HDAC4 has no effect on the global acetylation profile of the neonatal brain (AcetylScan proteomics), and HDAC4 knockout has no effect on global transcription in the postnatal murine brain. AcetylScan immunoaffinity proteomics, Affymetrix transcriptome arrays, HDAC4 knockout mice PloS one Medium 24278330
2013 HDAC4 directly interacts with ATF4; overexpression of HDAC4 retains ATF4 in the cytoplasm and inhibits ATF4 transcriptional activity. This interaction protects cells from ER stress-induced apoptosis by inhibiting CHOP and TRB3 upregulation downstream of ATF4. Co-immunoprecipitation (HDAC4-ATF4), subcellular fractionation, transcriptional reporter assays, overexpression/knockdown Cellular signalling Medium 24308964
2014 PTH triggers ubiquitination of HDAC4 via Smurf2 E3 ligase in osteoblasts, leading to HDAC4 degradation and release of MEF2c, which then transactivates the Rankl promoter. Conversely, sympathetic signaling promotes HDAC4 nuclear accumulation and association with ATF4 to increase Rankl expression, demonstrating that HDAC4 differentially integrates two extracellular cues to regulate osteoclast differentiation. Ubiquitination assays, co-immunoprecipitation (HDAC4-ATF4, HDAC4-MEF2c), genetic mouse models, Rankl promoter reporter assays The Journal of cell biology High 24934156
2014 HDAC4 integrates PTH signaling to inhibit chondrocyte hypertrophy: PTHrP reduces HDAC4 phosphorylation at 14-3-3-binding sites, allowing HDAC4 nuclear translocation where it represses MEF2 and Runx2, inhibiting chondrocyte hypertrophy. HDAC5 acts as a redundant mediator; combined HDAC4/HDAC5 knockout fully blocks PTHrP action in vivo. Multiple mouse genetic models (conditional KOs, double KOs), phosphorylation analysis, in vivo growth plate phenotyping JCI insight High 30843886
2015 SIK2 directly phosphorylates HDAC4 in adipocytes; HDAC4 interacts with SIK2 and PP2A. PKA-mediated phosphorylation of SIK2 on Ser358 reduces binding of CRTCs and PP2A to SIK2. Silencing HDAC4 increases GLUT4 protein levels and glucose uptake. Co-immunoprecipitation (SIK2-HDAC4-PP2A), phosphorylation analysis, siRNA knockdown, glucose uptake assay, SIK2 S358A mutant Journal of cell science Medium 25472719
2015 HDAC4 is required for appropriate transcriptional responses in sensory neurons after injury. Conditional HDAC4 knockout in sensory neurons reduces Calca and Trpv1 expression after injury, and reduces thermal hypersensitivity in an inflammatory pain model (CFA), identifying HDAC4 as a mediator of inflammation-induced thermal hypersensitivity. Conditional knockout mice, transcriptional analysis (qPCR), capsaicin sensitivity assay, CFA inflammatory pain model FASEB journal High 25903105
2015 Sumoylation of HDAC4 at K559 promotes its ubiquitin-dependent proteasomal degradation in cardiomyocytes during hypoxia/reoxygenation; disruption of HDAC4 sumoylation impairs ubiquitination and leads to HDAC4 accumulation and enhanced cardiomyocyte susceptibility to injury. Sumoylation mutant (K559R) stable cell lines, ubiquitination assays, proteasome inhibitor (MG132), adenoviral HDAC4 overexpression in cardiomyocytes Journal of cellular physiology Medium 25475100
2016 CDKL5 directly phosphorylates HDAC4, and CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention. In the absence of CDKL5, hypophosphorylated HDAC4 translocates to the nucleus of neural precursor cells, binds chromatin and MEF2A, reduces histone 3 acetylation, and alters neuronal gene expression, impairing neuronal survival and maturation. In vitro phosphorylation assay (CDKL5 on HDAC4), Cdkl5 knockout mouse, immunoprecipitation, ChIP, LMK235 pharmacological inhibition, rescue by re-expression Human molecular genetics High 27466189
2016 HDAC4 delays cellular senescence by stabilizing SIRT1: HDAC4 overexpression enhances SIRT1 sumoylation, increasing SIRT1 protein stability. HDAC4 knockdown leads to premature senescence in human fibroblasts. Overexpression and knockdown in human fibroblasts, sumoylation assay, protein stability analysis Clinical and experimental pharmacology & physiology Low 26414199
2017 HDAC4 suppresses innate immune responses by interacting with the kinase domains of TBK1 and IKKε, blocking phosphorylation of IRF3 at Ser386 and Ser396, thereby inhibiting IRF3 nuclear translocation and IFN-β expression. IFN-β stimulates HDAC4 expression, establishing a negative feedback loop. Co-immunoprecipitation (HDAC4-TBK1, HDAC4-IKKε), IRF3 phosphorylation assays, nuclear translocation assays, IFN-β reporter Journal of molecular cell biology Medium 29800227
2018 HDAC4 mediates FoxO3a deacetylation in vascular endothelial cells, increasing FoxO3a transcriptional activity and promoting expression of downstream autophagic targets, thereby activating autophagy and Ang II-induced vascular inflammation. Loss of HDAC4 inhibits FoxO3a deacetylation, reducing autophagy and inflammation. siRNA knockdown, FoxO3a siRNA, autophagy inhibitor, in vitro and in vivo Ang II models, LC3-II western blotting Cardiovascular research Medium 29529137
2018 HDAC4 regulates satellite cell proliferation and differentiation by targeting P21 and Sharp1 genes. Conditional inactivation of HDAC4 in Pax7+ satellite cells blocks differentiation, and reducing P21 or Sharp1 expression in HDAC4-KO satellite cells rescues the molecular pathway, identifying these as direct HDAC4 targets. Tamoxifen-inducible conditional HDAC4 KO in Pax7+ cells, RNA-sequencing, rescue experiments with siRNA for P21 and Sharp1 Scientific reports High 29472596
2019 HDAC4 deacetylates three non-histone substrates in skeletal muscle: myosin heavy chain, PGC-1α, and Hsc70. HDAC4 inhibition prevents denervation-induced loss of myosin heavy chain isoforms and blocks MuRF1-dependent ubiquitination. PGC-1α directly interacts with class IIa HDACs. Hsc70 deacetylation by HDAC4 affects its chaperone activity. Selective class IIa HDAC inhibitors, genetic knockdown, in vitro deacetylation assays, co-immunoprecipitation (PGC-1α with HDACs), denervation mouse model Cell reports High 31618641
2019 HDAC4 and HDAC5 form a complex with the transcription factor DREAM; this complex is recruited to the NCX3 promoter and mediates histone deacetylation to epigenetically repress NCX3 gene transcription. After stroke, DREAM/HDAC4/HDAC5 recruitment to ncx3 is increased, reducing NCX3 expression. Co-immunoprecipitation (HDAC4/HDAC5-DREAM complex), ChIP, siRNA knockdown, class IIa HDAC inhibitor MC1568, ischemic stroke rat model Journal of cerebral blood flow and metabolism Medium 31696766
2019 In mouse brain and HD mouse models, endogenous Hdac4 interactome (characterized by affinity purification-MS) is enriched in vesicular trafficking and synaptic functions. Hdac4 interactions in the striatum show polyQ-length dependence in symptomatic HD mice, while Hdac5 interactions do not, indicating a unique interaction network for Hdac4 in HD pathology. The WASH complex is validated as an Hdac4 interactor. Affinity purification-mass spectrometry (endogenous Hdac4 interactome), comparison across HD mouse series (Q20 vs Q140), co-IP validation of WASH complex interaction Molecular & cellular proteomics Medium 31040226
2019 HDAC4 mutations (p.His227Arg, p.Asp234Asn, p.Glu374Lys) disrupt FoxO1 deacetylation in pancreatic β-cells, causing nuclear exclusion of acetylated FoxO1, decreased insulin secretion, and downregulation of β-cell-specific transcription factors, resulting in diabetes. Exome sequencing, Sanger sequencing, insulin secretion assay, immunostaining, western blot for FoxO1 acetylation and localization in Min6/SJ cell lines transfected with mutant HDAC4 Molecular genetics & genomic medicine Medium 30968599
2019 MKK7 transcription in glioma cells depends on HDAC4 activity: HDAC4 directly deacetylates SP1 and KLF5, and the HDAC4-SP1-KLF5 complex upregulates MKK7 transcription. HDAC4 inhibition causes accumulation of acetylated SP1 and KLF5, switching the complex to a transcriptional repressor of MKK7, reducing JNK/c-Jun signaling. ChIP, co-immunoprecipitation, deacetylation assays, dominant-negative SP1, siRNA, HDAC4 inhibitor LMK235, xenograft mouse model International journal of cancer Medium 30963560
2020 Nox4-derived H2O2 oxidizes HDAC4 cysteine residues and increases HDAC4 phosphorylation on Ser632. Oxidation disrupts the HDAC4/Mef2A complex, de-repressing Mef2A. Overexpression of redox-insensitive HDAC4 mutant does not affect endothelial tube formation, while wild-type HDAC4 overexpression reduces tube formation that is rescued by H2O2 or Nox4 co-expression. Nox4 overexpression system (HEK293 inducible), H2O2 treatment, co-immunoprecipitation (HDAC4-Mef2A), redox-insensitive HDAC4 mutant, endothelial tube formation assay Redox biology Medium 32818796
2020 PKA-dependent phosphorylation of HDAC4 at S265/266 promotes HDAC4 nuclear retention in cardiomyocytes, opposing CaMKII-dependent nuclear export. The two kinase pathways compete to regulate HDAC4 nuclear localization in adult cardiomyocytes, with PKA effects predominating early and CaMKII effects predominating with prolonged stimuli. In failing cardiomyocytes CaMKII-dependent effects predominate. Confocal live imaging, HDAC4 S265/266A phosphorylation mutant, CaMKII and PKA inhibitors, isoproterenol/forskolin stimulation, adult mouse/rabbit/human cardiomyocytes Basic research in cardiology High 33590335
2021 HDAC4 nuclear localization in Drosophila neurons impairs mushroom body morphogenesis via MEF2, but impairs long-term memory independently of MEF2 (MEF2-binding site mutation does not rescue memory deficits). Nuclear HDAC4 sequesters MEF2 into punctate nuclear foci but does not alter MEF2 activity on memory-related transcription. Nuclear and cytoplasmic HDAC4 mutants expressed in Drosophila brain, MEF2 binding site mutation, MEF2 RNAi, memory behavioral assays, morphological analysis Frontiers in molecular neuroscience Medium 33859551
2022 HDAC4 deacetylates glutaminase (GAC) at Lys311, which inhibits GAC interaction with TRIM21 E3 ubiquitin ligase, thereby reducing K63-linked ubiquitination of GAC and maintaining GAC activity in non-small cell lung cancer. GAC K311Q (acetylation-mimicking) mutation decreases cancer cell proliferation. In vitro deacetylation assay, co-immunoprecipitation (GAC-TRIM21, GAC-HDAC4), site-directed mutagenesis (K311), ubiquitination assays International journal of biological sciences High 35864951
2022 ALKBH5 demethylates and stabilizes Hdac4 mRNA (m6A demethylation). HDAC4 protein interacts with and deacetylates FoxO3, increasing FoxO3 expression and activity, driving denervation-induced muscle atrophy. Specific Alkbh5 deletion in skeletal muscles prevents FoxO3 activation and protects from denervation atrophy. m6A-seq, mass spectrometry, co-immunoprecipitation (HDAC4-FoxO3), half-life assay, luciferase reporter, gain/loss-of-function in mice, mRNA stability assay Journal of cachexia, sarcopenia and muscle High 35142084
2022 Cytoplasmic HDAC4 in dystrophic muscles mediates the membrane repair mechanism; HDAC4 deletion in dystrophic muscles worsens DMD pathology including impaired membrane repair, satellite cell survival, and muscle regeneration. HDAC4 expression correlates with Trim72 mRNA levels and stabilizes Trim72 mRNA, partially independently of deacetylase activity. Restoration of cytoplasmic HDAC4 rescues the phenotype in vivo. Conditional HDAC4 KO in mdx dystrophic mice, histological and functional analyses, satellite cell differentiation assays, Trim72 ectopic expression rescue, cytoplasmic HDAC4 rescue Journal of cachexia, sarcopenia and muscle High 35170869
2022 HDAC4 deacetylates LHPP at K6, promoting TRIM21-mediated K48-linked ubiquitination and degradation of LHPP in nasopharyngeal carcinoma, thereby activating TYK2-STAT1 phosphorylation and promoting tumor progression. Co-immunoprecipitation (HDAC4-LHPP, LHPP-TRIM21), in vitro deacetylation assay, ubiquitination assay, site-directed mutagenesis (K6), xenograft mouse model Cancer letters Medium 37023940
2022 SP1 binds the HDAC4 promoter to upregulate HDAC4 expression; HDAC4 promotes deacetylation of HMGB1 to reduce HMGB1 nuclear export and inflammatory signaling, thereby reducing intestinal barrier dysfunction and inflammation in sepsis. ChIP (SP1 at HDAC4 promoter), co-immunoprecipitation (HDAC4-HMGB1), gain/loss-of-function in cell lines and septic mice, HDAC4 acetylation assay Journal of innate immunity Medium 35780770
2022 HDAC4 deacetylates GSDMD at Lys248, inhibiting GSDMD-mediated pyroptosis. HDAC4-mediated deacetylation of GSDMD impairs its ubiquitination, suppressing pyroptosis. Phosphorylation of HDAC4 is required for its ability to deacetylate GSDMD; PP1α and PP1γ dephosphorylate HDAC4, nullifying its deacetylase activity on GSDMD. In vitro deacetylation assay, co-immunoprecipitation (HDAC4-GSDMD, HDAC4-PP1), GSDMD K248 mutagenesis, ubiquitination assays, pyroptosis assays in vitro and in vivo Cell death & disease High 38326336
2023 HDAC4 forms a complex with HDAC1/HDAC2 that erases H2BK120 acetylation, modulating DNA repair by homologous recombination. HDAC4 deficiency leads to H2BK120ac accumulation, impaired BRCA1 and CtIP recruitment to DNA damage sites, DNA damage accumulation, and cellular senescence. In senescent cells, increased proteasomal degradation of HDAC4 disassembles this complex. Co-immunoprecipitation (HDAC4/HDAC1/HDAC2 complex), ChIP (BRCA1, CtIP, γH2AX), H2BK120ac analysis, HDAC4 forced expression, proteasome inhibition, RAS-induced senescence model Nucleic acids research High 38874468
2023 HDAC4 interacts with and deacetylates RUNX2, promoting RUNX2 degradation; SIK3 forms a complex with HDAC4, directly phosphorylates HDAC4, and regulates its nuclear-cytoplasmic shuttling. In hippocampal neurons, SIK3-mediated HDAC4 phosphorylation facilitates synaptic plasticity gene expression by preventing HDAC4 recruitment to MEF2C/target gene promoters. Co-immunoprecipitation (SIK3-HDAC4), ChIP-qPCR, western blotting, virus-mediated gene transfer, electrophysiology, Morris Water Maze, AD mouse models Neuropsychopharmacology Medium 38057370
2024 HDAC4 and HDAC7 cooperatively regulate Th17 cell differentiation: HDAC4 interacts with transcription factor JunB to activate transcription of Il17a/f, while HDAC7 collaborates with Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress Il2. Pharmacological or genetic inhibition of Hdac4/7 mitigates Th17-mediated intestinal inflammation in a colitis mouse model. Co-immunoprecipitation (HDAC4-JunB, HDAC7-Aiolos-Smrt/Ncor1), conditional KO mice, ChIP, Il17a/f and Il2 reporter assays, colitis mouse model Proceedings of the National Academy of Sciences of the United States of America High 38657041
2014 HDAC4 promotes Pax7-dependent satellite cell (SC) proliferation and restricts adipogenesis during muscle regeneration. HDAC4-deficient SCs show reduced Pax7 and Pax7 target gene expression; HDAC4 regulates Lix1 as a Pax7 target gene required for SC proliferation. HDAC4 deficiency leads to defective SC proliferation and aberrant lipid accumulation with deregulated Prdm16 and miR-133. Conditional HDAC4 KO in satellite cells, gene expression analysis, muscle regeneration assays EMBO reports Medium 25205686
2024 CircCGNL1 interacts with NUDT4 phosphatase to promote HDAC4 dephosphorylation and nuclear translocation. Intranuclear HDAC4 deacetylates RUNX2, promoting RUNX2 degradation. RUNX2 normally inhibits GAMT transcription; RUNX2 degradation releases GAMT, which induces apoptosis via AMPK-AKT-Bad signaling, suppressing pancreatic cancer cell growth. RNA pulldown, co-immunoprecipitation (circCGNL1-NUDT4, HDAC4-RUNX2), GST-pulldown, deacetylation assay, dual-luciferase reporter, HDAC4 phosphorylation analysis Molecular cancer Medium 38297362
2012 CaMKIIδ2 phosphorylates HDAC4 (and HDAC5) in vascular smooth muscle cells (VSMCs) in a Ca2+-dependent manner. HDAC5 phosphorylation is regulated by HDAC4; suppression of HDAC4 prevents AngII- and PDGF-dependent phosphorylation of HDAC5. CaMKIIδ2-HDAC4/5 axis regulates MEF2 DNA binding activity and downstream target genes. Phosphorylation analysis, CaMKIIδ2 siRNA/inhibitor, co-immunoprecipitation, MEF2 DNA-binding assay, AngII/PDGF stimulation The Biochemical journal Medium 22360269
2020 PTHrP signals through the cAMP/PKA pathway to phosphorylate and inhibit salt-inducible kinases (SIK1, SIK2, SIK3), reducing HDAC4 phosphorylation at 14-3-3 binding sites and allowing HDAC4 nuclear translocation, where it represses Mef2 and Runx2 to inhibit chondrocyte hypertrophy. HDAC5 provides genetic redundancy when HDAC4 levels are low. Multiple mouse genetic models (SIK KOs, HDAC4/5 KOs, double KOs), HDAC4 phosphorylation analysis, in vivo growth plate phenotyping Bone High 33148508
2014 p38 MAPK promotes HDAC4 degradation in hypertrophic chondrocytes by stimulating caspase-3 activity, which cleaves HDAC4 at the Asp289 site, releasing Runx2 from HDAC4-mediated repression and promoting chondrocyte hypertrophy. Constitutively active MKK6 transgenic mice show decreased HDAC4 content in vivo. Dominant negative p38, p38 inhibitor, caspase-3 activity assays, HDAC4 D289 mutagenesis, constitutively active MKK6 transgenic mice, Runx2 promoter reporter Biochimica et biophysica acta High 25447540
2015 A short N-terminal domain of HDAC4 (not requiring the catalytic domain) is sufficient for photoreceptor neuroprotection in rd1 mice, suppressing multiple cell death pathways and preserving cone photoreceptors and visual function. Transgenic expression of HDAC4 N-terminal domain in rd1 mice, photoreceptor survival assays, visual function testing Nature communications Medium 26272629
2022 HDAC4 is required for TET2 protein expression in MDS/AML; HDAC4 knockout reduces MTSS1 expression with decreased 5hmC enrichment on the MTSS1 enhancer. Pan-HDAC inhibition (SAHA) decreases TET2 expression and global 5hmC, an effect mediated specifically through HDAC4. RNAi screen, HDAC4 knockout, 5hmC measurement, ChIP (5hmC at MTSS1 enhancer), pan-HDACi treatment in MDS/AML lines and transgenic mice Aging Medium 32726753

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 653 22802322
2014 HDAC4: mechanism of regulation and biological functions. Epigenomics 202 24579951
2010 Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. The Lancet. Oncology 186 20864405
2011 HDAC4 protein regulates HIF1α protein lysine acetylation and cancer cell response to hypoxia. The Journal of biological chemistry 177 21917920
2017 Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 164 28761118
2013 HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS biology 147 24302884
1993 HD4, a 180 kDa bullous pemphigoid antigen, is a major transmembrane glycoprotein of the hemidesmosome. Journal of biochemistry 138 8514739
2008 HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism. Oncogene 135 18850004
2008 HDAC4 and PCAF bind to cardiac sarcomeres and play a role in regulating myofilament contractile activity. The Journal of biological chemistry 132 18250163
2008 HDAC4 inhibits cell-cycle progression and protects neurons from cell death. Developmental neurobiology 122 18498087
2012 miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model. Proceedings of the National Academy of Sciences of the United States of America 112 23169640
2007 PP2A regulates HDAC4 nuclear import. Molecular biology of the cell 111 18045992
2001 Differential localization of HDAC4 orchestrates muscle differentiation. Nucleic acids research 109 11504882
2015 HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements. Frontiers in cellular neuroscience 90 25759639
2016 HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder. Human molecular genetics 83 27466189
2017 HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells. Cancer letters 82 28342984
2018 HDAC4 regulates vascular inflammation via activation of autophagy. Cardiovascular research 80 29529137
2015 SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes. Journal of cell science 79 25472719
2019 HDAC4 Controls Muscle Homeostasis through Deacetylation of Myosin Heavy Chain, PGC-1α, and Hsc70. Cell reports 74 31618641
2012 A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Molecular cell 62 22658415
2010 Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility. Molecular biology of the cell 61 21118993
2010 Regional and subcellular distribution of HDAC4 in mouse brain. The Journal of comparative neurology 55 20034059
2014 HDAC4 integrates PTH and sympathetic signaling in osteoblasts. The Journal of cell biology 53 24934156
2012 MEF2 is regulated by CaMKIIδ2 and a HDAC4-HDAC5 heterodimer in vascular smooth muscle cells. The Biochemical journal 53 22360269
2023 m6A methylation regulates hypoxia-induced pancreatic cancer glycolytic metabolism through ALKBH5-HDAC4-HIF1α positive feedback loop. Oncogene 51 37149664
2018 Long noncoding RNA MALAT1 regulates HDAC4-mediated proliferation and apoptosis via decoying of miR-140-5p in osteosarcoma cells. Cancer medicine 51 30094957
2022 N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner. Cell death discovery 49 35840562
2021 MicroRNA-200b-3p promotes endothelial cell apoptosis by targeting HDAC4 in atherosclerosis. BMC cardiovascular disorders 48 33845782
1998 De novo synthesis of amino acids by the ruminal bacteria Prevotella bryantii B14, Selenomonas ruminantium HD4, and Streptococcus bovis ES1. Applied and environmental microbiology 48 9687438
2021 HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell death & disease 44 33542203
2019 PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy. JCI insight 44 30843886
2018 HDAC4 regulates satellite cell proliferation and differentiation by targeting P21 and Sharp1 genes. Scientific reports 44 29472596
2014 HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration. EMBO reports 43 25205686
2015 HDAC4 degradation mediates HDAC inhibition-induced protective effects against hypoxia/reoxygenation injury. Journal of cellular physiology 42 25475100
2015 Combinations of Hd2 and Hd4 genes determine rice adaptability to Heilongjiang Province, northern limit of China. Journal of integrative plant biology 42 25557147
2019 Host HDAC4 regulates the antiviral response by inhibiting the phosphorylation of IRF3. Journal of molecular cell biology 41 29800227
2013 HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4. Cellular signalling 41 24308964
2018 HDAC4 in ischemic stroke: mechanisms and therapeutic potential. Clinical epigenetics 40 30208931
2018 Histone deacetylase HDAC4 promotes the proliferation and invasion of glioma cells. International journal of oncology 40 30272277
2018 MicroRNA-145-3p suppresses proliferation and promotes apotosis and autophagy of osteosarcoma cell by targeting HDAC4. Artificial cells, nanomedicine, and biotechnology 39 29893594
2022 HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3. British journal of cancer 38 35637410
2021 CaMKII and PKA-dependent phosphorylation co-regulate nuclear localization of HDAC4 in adult cardiomyocytes. Basic research in cardiology 38 33590335
2017 p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury. Frontiers in neuroscience 38 28154524
2016 HDAC4 stabilizes SIRT1 via sumoylation SIRT1 to delay cellular senescence. Clinical and experimental pharmacology & physiology 38 26414199
2021 Circular RNA circ_0008360 Inhibits the Proliferation, Migration, and Inflammation and Promotes Apoptosis of Fibroblast-Like Synoviocytes by Regulating miR-135b-5p/HDAC4 Axis in Rheumatoid Arthritis. Inflammation 37 34462830
2019 Hdac4 Interactions in Huntington's Disease Viewed Through the Prism of Multiomics. Molecular & cellular proteomics : MCP 33 31040226
2017 Role of Phosphorylated HDAC4 in Stroke-Induced Angiogenesis. BioMed research international 30 28127553
2015 HDAC4 is required for inflammation-associated thermal hypersensitivity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 25903105
2021 Paeoniflorin ameliorates ischemic injury in rat brain via inhibiting cytochrome c/caspase3/HDAC4 pathway. Acta pharmacologica Sinica 29 33976387
2020 circHIPK3 promotes proliferation and migration and invasion via regulation of miR‑637/HDAC4 signaling in osteosarcoma cells. Oncology reports 29 33416147
2013 HDAC4 does not act as a protein deacetylase in the postnatal murine brain in vivo. PloS one 29 24278330
2022 microRNA-124-3p attenuates myocardial injury in sepsis via modulating SP1/HDAC4/HIF-1α axis. Cell death discovery 28 35091534
2022 Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology. Journal of medicinal chemistry 28 36098485
2021 MiR-206 regulates the progression of osteoporosis via targeting HDAC4. European journal of medical research 27 33461610
2018 MiR-520b restrains cell growth by targeting HDAC4 in lung cancer. Thoracic cancer 27 30106218
2022 m6 A demethylase ALKBH5 drives denervation-induced muscle atrophy by targeting HDAC4 to activate FoxO3 signalling. Journal of cachexia, sarcopenia and muscle 26 35142084
2022 Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis. International journal of biological sciences 26 35864951
2021 Long non-coding RNA Mir22hg-derived miR-22-3p promotes skeletal muscle differentiation and regeneration by inhibiting HDAC4. Molecular therapy. Nucleic acids 26 33767916
2022 circ_0003204 regulates the osteogenic differentiation of human adipose-derived stem cells via miR-370-3p/HDAC4 axis. International journal of oral science 25 35729156
2006 [35S]GTPgammaS binding at the human dopamine D4 receptor variants hD4.2, hD4.4 and hD4.7 following stimulation by dopamine, epinephrine and norepinephrine. European journal of pharmacology 25 16423344
2023 HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications. Frontiers in molecular biosciences 24 36762207
2020 HDAC4 Knockdown Induces Preeclampsia Cell Autophagy and Apoptosis by miR-29b. Reproductive sciences (Thousand Oaks, Calif.) 24 32780359
2022 circ‑LRP6 contributes to osteosarcoma progression by regulating the miR‑141‑3p/HDAC4/HMGB1 axis. International journal of oncology 23 35211755
2019 The posttranslational modification of HDAC4 in cell biology: Mechanisms and potential targets. Journal of cellular biochemistry 23 31588631
2019 HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 23 31696766
2015 A short N-terminal domain of HDAC4 preserves photoreceptors and restores visual function in retinitis pigmentosa. Nature communications 23 26272629
2023 Low expression of the intestinal metabolite butyric acid and the corresponding memory pattern regulate HDAC4 to promote apoptosis in rat hippocampal neurons. Ecotoxicology and environmental safety 22 36812872
2022 Cytoplasmic HDAC4 regulates the membrane repair mechanism in Duchenne muscular dystrophy. Journal of cachexia, sarcopenia and muscle 22 35170869
2020 Oxidation of HDAC4 by Nox4-derived H2O2 maintains tube formation by endothelial cells. Redox biology 22 32818796
2019 MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma. International journal of cancer 22 30963560
2023 HDAC4 mediated LHPP deacetylation enhances its destabilization and promotes the proliferation and metastasis of nasopharyngeal carcinoma. Cancer letters 21 37023940
2017 HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation. Oncotarget 21 29152115
2014 Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes. Biochimica et biophysica acta 21 25447540
2004 HDAC4: a corepressor controlling bone development. Cell 21 15537533
2022 KLF7 Alleviates Atherosclerotic Lesions and Inhibits Glucose Metabolic Reprogramming in Macrophages by Regulating HDAC4/miR-148b-3p/NCOR1. Gerontology 20 35439761
2017 Novel role and regulation of HDAC4 in cocaine-related behaviors. Addiction biology 20 28635037
2024 Role of a novel circRNA-CGNL1 in regulating pancreatic cancer progression via NUDT4-HDAC4-RUNX2-GAMT-mediated apoptosis. Molecular cancer 19 38297362
2023 Berberine ameliorates contrast-induced acute kidney injury by regulating HDAC4-FoxO3a axis-induced autophagy: In vivo and in vitro. Phytotherapy research : PTR 19 37922559
2022 SP1 Promotes HDAC4 Expression and Inhibits HMGB1 Expression to Reduce Intestinal Barrier Dysfunction, Oxidative Stress, and Inflammatory Response after Sepsis. Journal of innate immunity 19 35780770
2021 Increased Abundance of Nuclear HDAC4 Impairs Neuronal Development and Long-Term Memory. Frontiers in molecular neuroscience 19 33859551
2000 Characterization of dopaminergic compounds at hD2short, hD4.2 and hD4.7 receptors in agonist-stimulated [35S]GTPgammaS binding assays. Naunyn-Schmiedeberg's archives of pharmacology 19 10832603
2022 ATF4-mediated microRNA-145/HDAC4/p53 axis affects resistance of colorectal cancer cells to 5-fluorouracil by regulating autophagy. Cancer chemotherapy and pharmacology 18 35312836
2022 Pharmacological and Genetic Inhibition of HDAC4 Alleviates Renal Injury and Fibrosis in Mice. Frontiers in pharmacology 18 35847036
2024 HDAC4 influences the DNA damage response and counteracts senescence by assembling with HDAC1/HDAC2 to control H2BK120 acetylation and homology-directed repair. Nucleic acids research 17 38874468
2019 HDAC4 gene silencing alleviates epilepsy by inhibition of GABA in a rat model. Neuropsychiatric disease and treatment 17 30787615
2018 Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53-dependent senescence and favors cell transformation. Molecular oncology 17 30315623
2024 Crosstalk of HDAC4, PP1, and GSDMD in controlling pyroptosis. Cell death & disease 16 38326336
2020 PTHrP targets salt-inducible kinases, HDAC4 and HDAC5, to repress chondrocyte hypertrophy in the growth plate. Bone 16 33148508
2024 Butyrate reduction and HDAC4 increase underlie maternal high fructose-induced metabolic dysfunction in hippocampal astrocytes in female rats. The Journal of nutritional biochemistry 15 38199310
2024 Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation. Proceedings of the National Academy of Sciences of the United States of America 15 38657041
2023 Ginsenoside Rh4 inhibits inflammation-related hepatocellular carcinoma progression by targeting HDAC4/IL-6/STAT3 signaling. Molecular genetics and genomics : MGG 15 37843550
2023 Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 15 38057370
2022 Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice. Nature communications 15 35169129
2017 HDAC4 is expressed on multiple T cell lineages but dispensable for their development and function. Oncotarget 15 28177888
2016 The Eating-Disorder Associated HDAC4A778T Mutation Alters Feeding Behaviors in Female Mice. Biological psychiatry 15 27884425
2019 Histone deacetylase 4 (HDAC4): a new player in anorexia nervosa? Molecular psychiatry 14 30742020
2019 HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion. Molecular genetics & genomic medicine 14 30968599
1996 Affinities and intrinsic activities of dopamine receptor agonists for the hD21 and hD4.4 receptors. European journal of pharmacology 14 8773470
2021 A Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer. Cancers 13 34359722
2020 HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML. Aging 13 32726753

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