Affinage

HDAC4

Histone deacetylase 4 · UniProt P56524

Length
1084 aa
Mass
119.0 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HDAC4 is a class IIa histone deacetylase that functions as a signal-regulated transcriptional co-repressor and non-histone protein deacetylase, integrating calcium, cAMP/PKA, and growth factor signaling to control differentiation, survival, and metabolic programs in muscle, bone, neurons, and immune cells. Its subcellular localization — the primary mode of regulation — is governed by CaMKII-dependent phosphorylation and 14-3-3 binding (promoting cytoplasmic retention), PP2A-mediated dephosphorylation and PKA-dependent phosphorylation (promoting nuclear accumulation), redox-sensitive oxidation, ABHD5-mediated proteolytic cleavage, and GSK3β/sumoylation-dependent proteasomal degradation (PMID:10523670, PMID:11504882, PMID:18045992, PMID:33590335, PMID:31742248, PMID:21118993). In the nucleus, HDAC4 represses transcription factors including MEF2, Runx2, Sp1, CREB, and RelB/p52 to control myogenesis, chondrocyte hypertrophy, neuronal gene expression, and myeloma cell survival; it also deacetylates non-histone substrates such as MEKK2, FoxO1/FoxO3, GAC, KLF5, LHPP, and HIF-1α, thereby regulating MAPK-driven muscle atrophy, glutamine metabolism, and hypoxic adaptation (PMID:22658415, PMID:35142084, PMID:35864951, PMID:28319066, PMID:30843886, PMID:26455434). In the cytoplasm, HDAC4 promotes retinal neuron survival through an N-terminal domain–dependent, deacetylase-independent mechanism and modulates huntingtin aggregation in Huntington's disease models (PMID:19131628, PMID:26272629, PMID:24302884).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1999 High

    Establishing that HDAC4 possesses intrinsic deacetylase activity and represses transcription through two independent domains — and that it directly interacts with MEF2C — defined it as a transcriptional co-repressor with a specific transcription-factor target.

    Evidence In vitro deacetylase assay, Gal4-tethered repression assays, and co-immunoprecipitation with MEF2C

    PMID:10523670

    Open questions at the time
    • Physiological substrates beyond histones were unknown
    • In vivo relevance of MEF2 repression was not tested
    • Other transcription-factor partners were not identified
  2. 2001 High

    Demonstrating that HDAC4 shuttles between cytoplasm and nucleus under CaMK control and that 14-3-3 binding mediates cytoplasmic retention established signal-regulated nucleocytoplasmic trafficking as the primary mode of HDAC4 regulation.

    Evidence Fluorescence localization in differentiating myoblasts, constitutively active CaMKIV, and co-immunoprecipitation with 14-3-3

    PMID:11504882

    Open questions at the time
    • The phosphatase returning HDAC4 to the nucleus was unidentified
    • Whether the same mechanism operated in non-muscle cells was unknown
  3. 2003 High

    Extending the CaMK-dependent nuclear export mechanism to hippocampal neurons showed that neuronal activity dynamically regulates HDAC4 localization, broadening its regulatory role beyond muscle.

    Evidence Live-cell imaging in cultured hippocampal neurons with pharmacological CaMK inhibition

    PMID:12641737

    Open questions at the time
    • Downstream transcriptional targets in neurons were not identified
    • Whether HDAC4 had cytoplasmic functions in neurons was unknown
  4. 2007 High

    Identification of PP2A as the phosphatase that dephosphorylates HDAC4 and drives its nuclear import completed the kinase–phosphatase toggle controlling HDAC4 localization.

    Evidence In vitro binding and pulldown, RNAi of PP2A subunits, phospho-mimetic S298E mutant blocking nuclear import

    PMID:18045992

    Open questions at the time
    • How upstream signals regulate PP2A activity toward HDAC4 was unclear
    • Whether additional kinases beyond CaMKs contributed was unknown
  5. 2008 High

    Showing that HDAC4 represses p21 via Sp1 (not p53) and deacetylates histones at the p21 promoter identified a non-MEF2 transcription-factor partner and a specific tumor-suppressor gene target.

    Evidence ChIP at the p21 promoter, co-immunoprecipitation with Sp1, siRNA knockdown, reporter assays

    PMID:18850004

    Open questions at the time
    • Genome-wide targets beyond p21 were not mapped
    • Whether Sp1-dependent repression was tissue-specific was untested
  6. 2009 High

    Discovery that cytoplasmic HDAC4 promotes retinal neuron survival partly via HIF-1α established a deacetylase-independent, cytoplasmic pro-survival function distinct from its nuclear repressor role.

    Evidence AAV-mediated overexpression and knockdown in mouse retina, cytoplasm-restricted HDAC4 mutants in rd1 degeneration model

    PMID:19131628

    Open questions at the time
    • The molecular mechanism of cytoplasmic neuroprotection was not defined
    • Whether the N-terminal domain alone was sufficient was untested
  7. 2010 High

    Demonstrating that GSK3β phosphorylates HDAC4 at S298 to trigger ubiquitin-proteasomal degradation added a degradation-based layer of HDAC4 regulation beyond nucleocytoplasmic shuttling.

    Evidence In vitro kinase assay, ubiquitination assays, MG132 treatment, site-directed mutagenesis, motility assays

    PMID:21118993

    Open questions at the time
    • The E3 ubiquitin ligase responsible was not identified in this study
    • Relationship between GSK3β- and CaMK-mediated phosphorylation was unclear
  8. 2012 High

    Two studies resolved critical pathway connections: ATM was shown to restrain PP2A activity to keep HDAC4 cytoplasmic in neurons (nuclear HDAC4 causing neurodegeneration via MEF2A/CREB), and HDAC4 was found to deacetylate the non-histone substrate MEKK2 to activate MAPK-AP1 signaling in denervated muscle atrophy.

    Evidence ATM-KO mouse neurons with Co-IP/ChIP (HDAC4–MEF2A/CREB); in vitro deacetylation of MEKK2, genetic epistasis with AP1 in denervation model

    PMID:22466704 PMID:22658415

    Open questions at the time
    • Full spectrum of non-histone substrates was unknown
    • Whether MEKK2 deacetylation occurs in tissues beyond skeletal muscle was untested
  9. 2013 High

    HDAC4 was shown to associate with mutant huntingtin in a polyQ-length-dependent manner; genetic HDAC4 reduction delayed cytoplasmic aggregate formation and rescued neuronal function, establishing HDAC4 as a modifier of Huntington's disease pathology through a cytoplasmic mechanism.

    Evidence Co-IP, immunofluorescence co-localization, genetic knockdown in HD mouse models with electrophysiological and behavioral rescue

    PMID:24302884

    Open questions at the time
    • Whether HDAC4 enzymatic activity is required for huntingtin aggregation was unresolved
    • The proteomic study finding no global acetylation changes in HDAC4-KO brain questioned in vivo deacetylase relevance
  10. 2014 High

    In osteoblasts, HDAC4 was positioned as an integrator of PTH and sympathetic signaling: PTH triggers Smurf2-mediated HDAC4 degradation to derepress MEF2c-driven Rankl, while sympathetic signals promote nuclear HDAC4–ATF4 complexes also driving Rankl, demonstrating how opposing signals converge on HDAC4 to control bone remodeling.

    Evidence Osteoblast-specific KO mice, Co-IP with MEF2c and ATF4, ubiquitination by Smurf2, promoter reporters

    PMID:24934156

    Open questions at the time
    • Whether HDAC4 deacetylase activity is required for Rankl regulation was not tested
    • Redundancy with HDAC5 in this context was not resolved
  11. 2015 High

    A short N-terminal HDAC4 fragment was shown to be more neuroprotective than full-length HDAC4, suppressing multiple cell death pathways and partially restoring visual function in rd1 mice, establishing that HDAC4's pro-survival activity resides in a deacetylase-independent N-terminal domain.

    Evidence Transgenic N-terminal HDAC4 fragment expression in rd1 mice, ERG recordings, photoreceptor counts

    PMID:26272629

    Open questions at the time
    • Direct molecular targets of the N-terminal fragment were not identified
    • Whether this fragment functions in non-retinal neurodegeneration was unknown
  12. 2015 Medium

    Sumoylation of HDAC4 at K559 was shown to be a prerequisite for its ubiquitination and proteasomal degradation, adding a post-translational modification crosstalk layer; SIK2 was identified as a kinase phosphorylating HDAC4 in adipocytes to control GLUT4 and glucose uptake.

    Evidence K559R sumoylation-deficient mutant with ubiquitination assays (cardiomyocytes); Co-IP of SIK2–HDAC4 with siRNA and glucose uptake assays (adipocytes)

    PMID:25472719 PMID:25475100

    Open questions at the time
    • The SUMO E3 ligase for HDAC4 was not identified
    • Direct in vitro phosphorylation of HDAC4 by SIK2 was not demonstrated in the adipocyte study
  13. 2019 High

    Multiple studies converged to define HDAC4's physiological non-histone substrates and new regulatory inputs: HDAC4 deacetylates MHC (promoting degradation via MuRF1), PGC-1α, and Hsc70 in skeletal muscle; deacetylates FoxO1 in pancreatic β-cells (mutations impairing this cause nonautoimmune diabetes); is cleaved by ABHD5 protease to produce a cardioprotective N-terminal fragment; and is regulated by Akt-dependent nuclear import after denervation and by PTHrP/SIK-dependent dephosphorylation in chondrocytes.

    Evidence Selective class IIa HDAC inhibitors and in vitro deacetylation assays (muscle substrates); patient mutations with functional validation (β-cells); reconstituted in vitro ABHD5 cleavage and cardiac gene therapy (heart); genetic mouse models for Akt and PTHrP/SIK pathways

    PMID:30843886 PMID:30968599 PMID:31320633 PMID:31618641 PMID:31742248

    Open questions at the time
    • Structural basis for ABHD5 cleavage specificity was unknown
    • Whether diabetes-associated HDAC4 mutations affect non-FoxO1 substrates was untested
    • Complete inventory of non-histone substrates across tissues remained incomplete
  14. 2020 Medium

    Nox4-derived H₂O₂ was shown to oxidize HDAC4 cysteine residues and increase Ser632 phosphorylation, causing dissociation from MEF2A and derepression of angiogenic gene programs, establishing redox regulation as an additional input controlling HDAC4–MEF2 interaction.

    Evidence Nox4 overexpression, H₂O₂ treatment, redox-insensitive HDAC4 mutant, Co-IP with MEF2A, HUVEC tube formation

    PMID:32818796

    Open questions at the time
    • The specific cysteine residues oxidized were not fully mapped
    • In vivo relevance of redox regulation was not demonstrated
  15. 2021 High

    CaMKII and PKA were shown to compete for control of HDAC4 localization in cardiomyocytes (PKA promoting nuclear accumulation via Ser265/266), with CaMKII-dependent export predominating in heart failure; additionally, HDAC4 was found to complex with RelB/p52 to maintain repressive chromatin at proapoptotic genes in myeloma, and to deacetylate KLF5 to promote airway inflammation.

    Evidence Live confocal imaging with phospho-site mutants in cardiomyocytes; reciprocal Co-IP and ChIP of HDAC4–RelB at Bim/BMF loci; Co-IP of HDAC4–KLF5 with ChIP in bronchial epithelium

    PMID:26455434 PMID:33590335 PMID:34118928

    Open questions at the time
    • How the PKA vs CaMKII balance shifts during heart failure progression was unclear
    • Whether RelB–HDAC4 complexes form in non-myeloma contexts was unknown
  16. 2022 High

    HDAC4 was shown to deacetylate glutaminase (GAC) at K311 to prevent TRIM21-mediated ubiquitination, promoting glutamine metabolism and lung cancer tumorigenesis; and to deacetylate FoxO3 downstream of ALKBH5-stabilized Hdac4 mRNA, driving muscle atrophy; and to deacetylate LHPP at K6 to activate TYK2-STAT1 signaling in NPC.

    Evidence In vitro deacetylation assays and site-directed mutagenesis for GAC and LHPP; Co-IP of HDAC4–FoxO3 with m6A-MeRIP and muscle-specific KO for atrophy

    PMID:35142084 PMID:35864951 PMID:37023940

    Open questions at the time
    • Whether HDAC4 deacetylates GAC in normal vs. tumor tissues differentially was unknown
    • Structural basis for HDAC4 substrate selectivity among diverse non-histone targets remained unresolved
  17. 2023 Medium

    IL-1β signaling was shown to drive HDAC4 nuclear accumulation in HSV-1-infected neurons, where it associates with MeCP2 and promotes MeCP2 SUMOylation, repressing synaptic plasticity genes and causing cognitive impairment — revealing a neuroimmune context for HDAC4 nuclear action.

    Evidence Co-IP of HDAC4–MeCP2, SUMOylation assay, LTP recordings, Anakinra pharmacological blockade in infected neurons

    PMID:37261502

    Open questions at the time
    • Whether HDAC4 directly catalyzes MeCP2 SUMOylation or recruits a SUMO ligase was unclear
    • Generalizability beyond HSV-1 neuroinflammation was untested
  18. 2024 High

    HDAC4 was shown to interact with JunB in Th17 cells to facilitate Il17a/f transcriptional activation, establishing a pro-inflammatory transcriptional activator role for HDAC4 in adaptive immunity distinct from its canonical repressor functions.

    Evidence T-cell-specific genetic KO, Co-IP with JunB, ChIP, colitis mouse model

    PMID:38657041

    Open questions at the time
    • Whether HDAC4 deacetylase activity is required for JunB-dependent activation was not determined
    • The mechanism by which HDAC4 activates rather than represses transcription in this context was not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for HDAC4's selectivity among its numerous non-histone substrates, the molecular mechanism by which the N-terminal fragment confers neuroprotection, whether HDAC4 functions primarily as a scaffold rather than an enzyme in the brain (given the absence of global acetylation changes in KO), and how its transcriptional activator vs. repressor roles are contextually determined.
  • No structural model of HDAC4 bound to a non-histone substrate exists
  • Neuroprotective mechanism of N-terminal fragment is molecularly undefined
  • In vivo enzymatic contribution vs. scaffolding role remains unresolved across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0140096 catalytic activity, acting on a protein 6 GO:0042393 histone binding 3
Localization
GO:0005634 nucleus 7 GO:0005829 cytosol 4
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-4839726 Chromatin organization 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 1
Partners
14-3-3JUNBMEF2AMEF2CMEKK2PP2ARELBSP1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 HDAC4 possesses intrinsic histone deacetylase activity in its C-terminal domain and acts as a transcriptional co-repressor through two independent repression domains (N-terminal residues 1-208 and the deacetylase domain); it interacts with MEF2C through a small N-terminal region to downmodulate c-jun promoter activity. In vitro deacetylase assay, transcriptional repression assays with tethered HDAC4, co-immunoprecipitation with MEF2C Molecular and cellular biology High 10523670
2001 HDAC4 localizes to the cytoplasm during myoblast differentiation but relocates to the nucleus after fusion; nuclear HDAC4 suppresses the myogenic programme and MEF2-dependent transcription. CaMKIV activation prevents nuclear entry of HDAC4. HDAC4 binds 14-3-3 proteins in a phosphorylation-dependent manner, and this binding is responsible for its cytoplasmic retention. Fluorescence localization, overexpression/knockdown, constitutively active CaMKIV, co-immunoprecipitation with 14-3-3 Nucleic acids research High 11504882
2003 In hippocampal neurons, HDAC4 subcellular localization is dynamically regulated by neuronal activity: spontaneous electrical activity drives nuclear export of HDAC4, and this is partially blocked by the CaM kinase inhibitor KN-62, establishing CaM kinase-dependent nuclear export as the mechanism controlling HDAC4 localization in neurons. Live-cell imaging in cultured hippocampal neurons, pharmacological CaMK inhibition, calcium channel stimulation Journal of neurochemistry High 12641737
2007 PP2A (holoenzyme comprising Cα, Aα, and B/PR55α subunits) interacts with the N-terminus of HDAC4, dephosphorylates HDAC4, and controls HDAC4 nuclear import. Serine 298 within the PEST1 sequence is a key phosphorylation site; a phospho-mimetic S298E mutant is defective in nuclear import, and PP2A knockdown blocks nuclear import. In vitro and in vivo binding assays (Co-IP, pulldown), RNAi, okadaic acid treatment, site-directed mutagenesis, nuclear import assays Molecular biology of the cell High 18045992
2008 HDAC4 represses p21(WAF1/Cip1) expression through Sp1/Sp3 binding sites (not p53 sites); HDAC4 physically interacts with Sp1, binds the p21 proximal promoter, and reduces histone H3 acetylation there. siRNA knockdown, ChIP, Co-IP, reporter assays Oncogene High 18850004
2009 HDAC4 promotes survival of retinal neurons (rod photoreceptors and bipolar cells) through its activity in the cytoplasm, at least partly via HIF-1α; overexpression in a retinal degeneration mouse model prolonged photoreceptor survival. Conditional knockdown and overexpression in mouse retina (AAV-mediated), analysis of cytoplasm-restricted vs. nuclear HDAC4 mutants Science High 19131628
2009 HDAC4 represses VEGF expression in chondrosarcoma by modulating RUNX2 activity; reduced HDAC4 expression increases RUNX2 leading to increased VEGF and in vitro angiogenesis. siRNA knockdown, reporter assays, in vitro angiogenesis assay The Journal of biological chemistry Medium 19509297
2010 HDAC4 is degraded by the ubiquitin-proteasome system following serum starvation; GSK3β phosphorylates HDAC4 at serine 298 (with serine 302 as priming phosphate), targeting it for poly-ubiquitination and proteasomal degradation. This degradation regulates random cell motility. In vitro kinase assay (GSK3β), proteasome inhibitor (MG132), siRNA, site-directed mutagenesis, ubiquitination assays, motility assays Molecular biology of the cell High 21118993
2012 ATM deficiency causes nuclear accumulation of HDAC4 in neurons due to enhanced PP2A activity (which dephosphorylates HDAC4, preventing its cytoplasmic retention); nuclear HDAC4 binds chromatin and the transcription factors MEF2A and CREB, causing histone deacetylation and neurodegeneration. ATM normally phosphorylates and downregulates PP2A to keep HDAC4 cytoplasmic. Co-IP (HDAC4 with MEF2A, CREB), ChIP, ATM knockout mouse model, pharmacological/genetic HDAC4 inhibition, behavioral assays Nature medicine High 22466704
2012 HDAC4 activates MAP kinase signaling in denervated muscle by binding and promoting deacetylation/activation of MEKK2 (a MAP3K), which in turn activates AP1-dependent transcription driving the muscle atrophy program; this is independent of HDAC4's canonical transcriptional repressor activity. Co-IP, in vitro deacetylation assay, epistasis with AP1 inactivation, denervation mouse model, genetic knockouts Molecular cell High 22658415
2013 HDAC4 associates with huntingtin in a polyglutamine-length-dependent manner and co-localizes with cytoplasmic inclusions; genetic reduction of HDAC4 delayed cytoplasmic huntingtin aggregate formation, restored Bdnf transcript levels, and rescued neuronal and synaptic function in HD mouse models without affecting nuclear aggregation or global transcription. Co-IP, immunofluorescence co-localization, genetic knockdown (HD mouse models), behavioral/electrophysiological readouts PLoS biology High 24302884
2013 In the postnatal murine brain in vivo, absence of HDAC4 has no effect on global protein acetylation profiles (assessed by immunoaffinity proteomics) and no effect on global transcription, consistent with HDAC4 not functioning as a lysine deacetylase in this context. AcetylScan proteomic method (immunoaffinity-based), Affymetrix transcriptome arrays, HDAC4 KO mouse brain PloS one Medium 24278330
2014 HDAC4 integrates PTH and sympathetic signaling in osteoblasts: PTH triggers Smurf2-mediated ubiquitination and degradation of HDAC4, releasing MEF2c to transactivate the Rankl promoter; sympathetic signaling promotes nuclear accumulation of HDAC4 and its association with ATF4 to also increase Rankl expression, thereby controlling osteoclast differentiation. Co-IP (HDAC4 with MEF2c, ATF4), ubiquitination assay, Smurf2 identification, osteoblast-specific KO mice, promoter reporter assays The Journal of cell biology High 24934156
2014 HDAC4 is required for Pax7-dependent satellite cell proliferation and muscle regeneration; HDAC4-deficient satellite cells show reduced Pax7 and target gene expression, defective proliferation, aberrant lipid accumulation, and deregulated Prdm16/miR-133. Satellite cell-specific HDAC4 knockout, muscle regeneration assays, gene expression analysis EMBO reports Medium 25205686
2014 HDAC4 reduces histone H3 acetylation on the p21 proximal promoter via interaction with Sp1 to repress p21 and promote cancer cell proliferation; p21 knockdown rescues HDAC4 siRNA-induced cell cycle arrest and apoptosis. siRNA, ChIP, Co-IP, epistasis by p21 siRNA rescue, in vivo glioblastoma model PloS one Medium 24896240
2015 HDAC4 sumoylation at K559 is required for its ubiquitination and proteasomal degradation; disruption of sumoylation causes HDAC4 accumulation and impaired ubiquitination, enhancing susceptibility to hypoxia/reoxygenation injury in cardiomyocytes. Sumoylation-deficient mutant (K559R), proteasome inhibitor (MG132), ubiquitination assay, H/R injury readout Journal of cellular physiology Medium 25475100
2015 SIK2 directly phosphorylates HDAC4 in adipocytes; HDAC4, CRTC2, CRTC3, and PP2A all interact with SIK2. SIK2-mediated regulation of HDAC4 controls GLUT4 protein levels and glucose uptake in adipocytes. Co-IP (SIK2 with HDAC4, CRTCs, PP2A), siRNA knockdown, glucose uptake assay, phosphorylation analysis Journal of cell science Medium 25472719
2015 A short N-terminal domain of HDAC4 (not the deacetylase domain) suppresses multiple cell death pathways in photoreceptor degeneration, preserves rd1 rod photoreceptors more effectively than full-length HDAC4, prolongs cone survival, and partially restores visual function. Transgenic expression of N-terminal HDAC4 fragment in rd1 mice, ERG visual function assay, photoreceptor counting Nature communications High 26272629
2019 PKB/Akt activation promotes nuclear import of HDAC4 in denervated skeletal muscle and is required for epigenetic changes and synaptic gene upregulation after nerve injury; mTORC1 must be tightly balanced to allow dynamic autophagy changes. Genetic mouse models (constitutive Akt/mTORC1 activation/inhibition), nuclear import imaging, gene expression, neuromuscular endplate analysis Nature communications High 31320633
2019 HDAC4 deacetylates three non-histone substrates in skeletal muscle: myosin heavy chain (MHC), PGC-1α, and Hsc70. Deacetylation of MHC by HDAC4 promotes its degradation via the E3 ligase MuRF1; PGC-1α directly interacts with class IIa HDACs and its protein level is increased by selective inhibition; Hsc70 deacetylation by HDAC4 affects its chaperone activity. Selective class IIa HDAC inhibitors, genetic knockdown, in vitro deacetylation assay, Co-IP (PGC-1α with class IIa HDACs), mass spectrometry substrate identification Cell reports High 31618641
2019 ABHD5 acts as a serine protease that cleaves HDAC4, producing an N-terminal polypeptide (HDAC4-NT); this proteolytic product inhibits MEF2-dependent gene expression and controls glucose handling. ABHD5-deficiency leads to heart failure and reduced HDAC4-NT in the heart. In vitro and in vivo proteolytic cleavage assay, cardiac-specific gene therapy with HDAC4-NT, MEF2 reporter assays, ABHD5 KO mouse model Nature metabolism High 31742248
2019 PTHrP inhibits chondrocyte hypertrophy in vivo by reducing HDAC4 phosphorylation at 14-3-3 binding sites, causing HDAC4 nuclear translocation; nuclear HDAC4 blocks Mef2 and Runx2 activity, suppressing hypertrophy. HDAC5 acts redundantly with HDAC4 in mediating PTHrP signaling at birth. Multiple mouse genetics models (Hdac4-KO, Hdac5-KO, double-KO, Pthrp-KO), phosphorylation analysis, nuclear localization imaging JCI insight High 30843886
2019 HDAC4 mutations (p.His227Arg, p.Asp234Asn, p.Glu374Lys) in patients with nonautoimmune diabetes decrease insulin secretion and cause nuclear exclusion of acetylated FoxO1; HDAC4 normally deacetylates FoxO1, and these mutations disrupt FoxO1 deacetylation, thereby impairing β-cell function. Immunostaining, Western blot, insulin secretion assay, transfection of mutants in pancreatic β-cell lines, qRT-PCR Molecular genetics & genomic medicine Medium 30968599
2020 PTHrP/cAMP/PKA signaling inhibits SIK3 (and SIK1/2), reducing phosphorylation of HDAC4 at 14-3-3 binding sites, allowing HDAC4 nuclear translocation where it blocks both Mef2 and Runx2 to repress chondrocyte hypertrophy. Mouse genetics (Sik3 KO, Sik1/2/3 compound mutants, Hdac4/5 compound KO), phosphorylation assays Bone High 33148508
2021 In adult cardiomyocytes, CaMKII activation drives HDAC4 nuclear export while PKA activation drives HDAC4 nuclear accumulation; these effects are co-regulated and compete. PKA regulation requires Ser265/266. In failing cardiomyocytes, CaMKII-dependent effects predominate over PKA-dependent effects. Confocal live imaging, pharmacological kinase inhibitors/activators, HDAC4 phospho-site mutants (S265/266A), human/mouse/rabbit cardiomyocytes Basic research in cardiology High 33590335
2021 HDAC4 deacetylates KLF5, and the deacetylated KLF5 binds the Slug promoter to upregulate Slug expression, which increases CXCL12 in bronchial epithelial cells, promoting airway inflammation and bronchial smooth muscle cell proliferation/migration in asthma. IP assay, dual luciferase reporter assay, ChIP, siRNA, OVA mouse model Journal of translational medicine Medium 34118928
2021 In Drosophila, nuclear HDAC4 acts through MEF2 (sequestering it into punctate foci) to disrupt mushroom body morphogenesis, while nuclear HDAC4 impairs long-term memory through a MEF2-independent mechanism (MEF2 binding site mutation did not rescue memory deficits). Nuclear/cytoplasm-restricted HDAC4 mutants expressed in Drosophila brain, mushroom body morphology analysis, long-term memory assays, MEF2 binding site mutagenesis, MEF2 RNAi Frontiers in molecular neuroscience Medium 33859551
2021 HDAC4 forms a complex with RelB and p52 (NF-κB subunits) that maintains repressive chromatin around the proapoptotic genes Bim and BMF to control multiple myeloma survival; a HDAC4-mimetic polypeptide disrupts the RelB-HDAC4 complex and blocks MM growth. Co-IP (HDAC4 with RelB, p52), ChIP, dominant-negative peptide disruption, siRNA, cell viability assays Nature communications High 26455434
2022 HDAC4 deacetylates glutaminase (GAC) at Lys311; Lys311 acetylation stimulates interaction between GAC and the E3 ubiquitin ligase TRIM21, promoting K63-linked ubiquitination and inhibiting GAC activity. HDAC4-mediated deacetylation of GAC thus promotes glutamine metabolism and lung cancer tumorigenesis. In vitro deacetylation assay, Co-IP (GAC with TRIM21), ubiquitination assay, site-directed mutagenesis (K311Q), cell proliferation and tumor malignancy assays International journal of biological sciences High 35864951
2022 ALKBH5 demethylates and stabilizes Hdac4 mRNA (m6A demethylation); stabilized HDAC4 protein interacts with and deacetylates FoxO3, increasing FoxO3 expression and activity, thereby driving denervation-induced skeletal muscle atrophy. m6A-MeRIP-qPCR, mRNA half-life assay, Co-IP (HDAC4 with FoxO3), deacetylation assay, muscle-specific Alkbh5 KO mice, luciferase reporter Journal of cachexia, sarcopenia and muscle High 35142084
2022 HDAC4 promotes gastric cancer growth and metastasis by inhibiting MEF2A-driven transcription of ATG4B (by binding the ATG4B promoter), thereby preventing p62-dependent autophagic degradation of MEKK3 and activating p38 MAPK signaling. Downstream USF1 enhances HDAC4 expression creating a positive feedback loop. ChIP, dual-luciferase reporter, RNA-seq/GSEA, Co-IP, immunofluorescence, in vitro/in vivo functional assays British journal of cancer Medium 35637410
2022 HDAC4 deacetylates LHPP at K6, promoting TRIM21-mediated K48-linked ubiquitination and degradation of LHPP; this reduces LHPP-mediated inhibition of TYK2-STAT1 phosphorylation, promoting NPC proliferation and invasion. Co-IP, deacetylation assay, ubiquitination assay, site-directed mutagenesis (K6), HDAC4 KD, TRIM21 KD Cancer letters Medium 37023940
2020 Nox4-derived H2O2 oxidizes HDAC4 (at cysteine residues) and increases HDAC4 phosphorylation on Ser632; oxidized/phosphorylated HDAC4 dissociates from the Mef2A complex, de-repressing Mef2A and maintaining endothelial tube formation. A redox-insensitive HDAC4 mutant fails to restore tube formation. Overexpression of Nox4, H2O2 treatment, redox-insensitive HDAC4 mutant, Co-IP (HDAC4/Mef2A), HUVEC tube formation assay Redox biology Medium 32818796
2023 IL-1β signaling in HSV-1-infected neurons promotes nuclear accumulation of HDAC4, which associates with MeCP2; nuclear HDAC4 promotes MeCP2 SUMOylation, enhancing MeCP2 repressive activity and downregulating synaptic plasticity-related genes, leading to cognitive impairment. IL-1 receptor blockade with Anakinra prevents HDAC4 nuclear accumulation and the associated synaptic dysfunction. Immunofluorescence, Co-IP (HDAC4 with MeCP2), SUMOylation assay, gene expression analysis, LTP recording, Anakinra pharmacological blockade Cellular and molecular life sciences Medium 37261502
2017 Nuclear NAC1 binds HDAC4 and hinders its phosphorylation at Ser246, preventing nuclear export; nuclear HDAC4 accumulation leads to HIF-1α deacetylation, enhancing HIF-1α stabilization and transcriptional activity to promote glycolysis in hypoxic tumor cells. Co-IP (NAC1 with HDAC4), phosphorylation assay, deacetylation assay, nuclear localization imaging, xenograft model Oncogene Medium 28319066
2024 HDAC4 and HDAC7 are selectively induced in Th17 cells; HDAC4 interacts with JunB to facilitate transcriptional activation of Il17a/f, while HDAC7 collaborates with Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress Il2 during Th17 differentiation. T-cell lineage-specific genetic KO, Co-IP (HDAC4 with JunB; HDAC7 with Aiolos/Smrt/Ncor1-Hdac3), ChIP, gene expression analysis, colitis mouse model Proceedings of the National Academy of Sciences of the United States of America High 38657041

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 651 22802322
1999 HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Molecular and cellular biology 255 10523670
2003 Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. Journal of neurochemistry 250 12641737
2014 HDAC4: mechanism of regulation and biological functions. Epigenomics 200 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
2012 Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia. Nature medicine 174 22466704
2009 HDAC4 regulates neuronal survival in normal and diseased retinas. Science (New York, N.Y.) 165 19131628
2017 Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 160 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
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
2016 Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma. Molecular cancer therapeutics 101 27196750
2019 mTORC1 and PKB/Akt control the muscle response to denervation by regulating autophagy and HDAC4. Nature communications 95 31320633
2015 HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements. Frontiers in cellular neuroscience 89 25759639
2019 MIR145-3p promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting HDAC4. Autophagy 84 31242129
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
2014 Histone deacetylase HDAC4 promotes gastric cancer SGC-7901 cells progression via p21 repression. PloS one 63 24896240
2012 A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Molecular cell 61 22658415
2010 Ubiquitin-dependent degradation of HDAC4, a new regulator of random cell motility. Molecular biology of the cell 61 21118993
2017 lncRNA-MIAT regulates cell biological behaviors in gastric cancer through a mechanism involving the miR-29a-3p/HDAC4 axis. Oncology reports 59 29039602
2009 HDAC4 represses vascular endothelial growth factor expression in chondrosarcoma by modulating RUNX2 activity. The Journal of biological chemistry 57 19509297
2019 The lipid droplet-associated protein ABHD5 protects the heart through proteolysis of HDAC4. Nature metabolism 55 31742248
2010 Regional and subcellular distribution of HDAC4 in mouse brain. The Journal of comparative neurology 55 20034059
2015 Transcriptional repression by the HDAC4-RelB-p52 complex regulates multiple myeloma survival and growth. Nature communications 54 26455434
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
2018 Long noncoding RNA MALAT1 regulates HDAC4-mediated proliferation and apoptosis via decoying of miR-140-5p in osteosarcoma cells. Cancer medicine 51 30094957
2023 m6A methylation regulates hypoxia-induced pancreatic cancer glycolytic metabolism through ALKBH5-HDAC4-HIF1α positive feedback loop. Oncogene 48 37149664
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 47 9687438
2016 Heme Oxygenase-1 Controls an HDAC4-miR-206 Pathway of Oxidative Stress in Rhabdomyosarcoma. Cancer research 45 27488535
2022 N6-methyladenosine (m6A) methyltransferase METTL3 regulates sepsis-induced myocardial injury through IGF2BP1/HDAC4 dependent manner. Cell death discovery 44 35840562
2017 Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the HDAC4-HIF-1α axis. Oncogene 44 28319066
2021 HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target. Cell death & disease 43 33542203
2019 PTHrP targets HDAC4 and HDAC5 to repress chondrocyte hypertrophy. JCI insight 43 30843886
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
2014 HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration. EMBO reports 42 25205686
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
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
2021 Long non-coding RNA GAS5 suppresses rheumatoid arthritis progression via miR-128-3p/HDAC4 axis. Molecular and cellular biochemistry 38 33611674
2017 p38/Sp1/Sp4/HDAC4/BDNF Axis Is a Novel Molecular Pathway of the Neurotoxic Effect of the Methylmercury. Frontiers in neuroscience 38 28154524
2018 STAT1‑HDAC4 signaling induces epithelial‑mesenchymal transition and sphere formation of cancer cells overexpressing the oncogene, CUG2. Oncology reports 36 30226605
2013 Genomic pathway analysis reveals that EZH2 and HDAC4 represent mutually exclusive epigenetic pathways across human cancers. BMC medical genomics 35 24079712
2022 Urine-derived stem cells-extracellular vesicles ameliorate diabetic osteoporosis through HDAC4/HIF-1α/VEGFA axis by delivering microRNA-26a-5p. Cell biology and toxicology 32 35554780
2017 Role of Phosphorylated HDAC4 in Stroke-Induced Angiogenesis. BioMed research international 30 28127553
2023 Interleukin 1β triggers synaptic and memory deficits in Herpes simplex virus type-1-infected mice by downregulating the expression of synaptic plasticity-related genes via the epigenetic MeCP2/HDAC4 complex. Cellular and molecular life sciences : CMLS 29 37261502
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
2021 Paeoniflorin ameliorates ischemic injury in rat brain via inhibiting cytochrome c/caspase3/HDAC4 pathway. Acta pharmacologica Sinica 28 33976387
2017 Increased EGFR expression induced by a novel oncogene, CUG2, confers resistance to doxorubicin through Stat1-HDAC4 signaling. Cellular oncology (Dordrecht, Netherlands) 28 28776259
2022 Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology. Journal of medicinal chemistry 27 36098485
2019 Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor. American journal of medical genetics. Part A 27 30848064
2018 MiR-520b restrains cell growth by targeting HDAC4 in lung cancer. Thoracic cancer 27 30106218
2015 TGF-β1 Reduces miR-29a Expression to Promote Tumorigenicity and Metastasis of Cholangiocarcinoma by Targeting HDAC4. PloS one 27 26441331
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 MiR-206 regulates the progression of osteoporosis via targeting HDAC4. European journal of medical research 26 33461610
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
2021 HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 expression through KLF5 deacetylation. Journal of translational medicine 25 34118928
2020 miR-873-3p targets HDAC4 to stimulate matrix metalloproteinase-13 expression upon parathyroid hormone exposure in rat osteoblasts. Journal of cellular physiology 25 31960421
2021 Long non-coding RNA Mir22hg-derived miR-22-3p promotes skeletal muscle differentiation and regeneration by inhibiting HDAC4. Molecular therapy. Nucleic acids 24 33767916
2020 STVNa Attenuates Isoproterenol-Induced Cardiac Hypertrophy Response through the HDAC4 and Prdx2/ROS/Trx1 Pathways. International journal of molecular sciences 24 31968660
2020 HDAC4 Knockdown Induces Preeclampsia Cell Autophagy and Apoptosis by miR-29b. Reproductive sciences (Thousand Oaks, Calif.) 24 32780359
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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
2018 The Deletion of Hdac4 in Mouse Osteoblasts Influences Both Catabolic and Anabolic Effects in Bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 23 29544022
2015 A short N-terminal domain of HDAC4 preserves photoreceptors and restores visual function in retinitis pigmentosa. Nature communications 23 26272629
2020 Oxidation of HDAC4 by Nox4-derived H2O2 maintains tube formation by endothelial cells. Redox biology 22 32818796
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 21 36812872
2023 HDAC4 mediated LHPP deacetylation enhances its destabilization and promotes the proliferation and metastasis of nasopharyngeal carcinoma. Cancer letters 21 37023940
2014 Mitogen-activated protein kinase p38 induces HDAC4 degradation in hypertrophic chondrocytes. Biochimica et biophysica acta 21 25447540
2022 KLF7 Alleviates Atherosclerotic Lesions and Inhibits Glucose Metabolic Reprogramming in Macrophages by Regulating HDAC4/miR-148b-3p/NCOR1. Gerontology 20 35439761
2020 Cyclo-RGD Truncated Polymeric Nanoconstruct with Dendrimeric Templates for Targeted HDAC4 Gene Silencing in a Diabetic Nephropathy Mouse Model. Molecular pharmaceutics 20 32453574
2019 MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma. International journal of cancer 20 30963560
2017 Novel role and regulation of HDAC4 in cocaine-related behaviors. Addiction biology 20 28635037
2017 HDAC-4 regulates claudin-2 expression in EGFR-ERK1/2 dependent manner to regulate colonic epithelial cell differentiation. Oncotarget 20 29152115
2021 Increased Abundance of Nuclear HDAC4 Impairs Neuronal Development and Long-Term Memory. Frontiers in molecular neuroscience 19 33859551
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2023 Berberine ameliorates contrast-induced acute kidney injury by regulating HDAC4-FoxO3a axis-induced autophagy: In vivo and in vitro. Phytotherapy research : PTR 18 37922559
2022 ATF4-mediated microRNA-145/HDAC4/p53 axis affects resistance of colorectal cancer cells to 5-fluorouracil by regulating autophagy. Cancer chemotherapy and pharmacology 17 35312836
2022 Pharmacological and Genetic Inhibition of HDAC4 Alleviates Renal Injury and Fibrosis in Mice. Frontiers in pharmacology 17 35847036
2019 HDAC4 gene silencing alleviates epilepsy by inhibition of GABA in a rat model. Neuropsychiatric disease and treatment 17 30787615
2020 PTHrP targets salt-inducible kinases, HDAC4 and HDAC5, to repress chondrocyte hypertrophy in the growth plate. Bone 16 33148508
2018 Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53-dependent senescence and favors cell transformation. Molecular oncology 16 30315623
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
2021 Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. HGG advances 15 33537682
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
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2019 HDAC4 mutations cause diabetes and induce β-cell FoxO1 nuclear exclusion. Molecular genetics & genomic medicine 14 30968599