Affinage

HDAC8

Histone deacetylase 8 · UniProt Q9BY41

Length
377 aa
Mass
41.8 kDa
Annotated
2026-04-28
100 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HDAC8 is a class I, Zn²⁺-dependent lysine deacetylase that removes acetyl groups from both histone and non-histone substrates to regulate chromatin state, cohesin recycling, and cell signaling. Its catalytic activity, dependent on conserved active-site histidine residues, targets histone H3K27 and H4 to repress transcription at specific loci—often in concert with EZH2 or the FACT complex (SSRP1/SUPT16H)—and deacetylates non-histone substrates including SMC3 (enabling cohesin recycling during the cell cycle), p53 (modulating apoptosis in hematopoietic stem cells and AML), c-Jun (increasing AP-1 transcriptional activity), PKM2 (promoting its nuclear translocation and β-catenin/CCND1 signaling), and EP300 (inactivating this acetyltransferase to redirect chromatin accessibility) (PMID:10926844, PMID:27072133, PMID:33827976, PMID:29084772, PMID:30987999, PMID:33279948, PMID:38030596, PMID:34021025). Loss-of-function mutations in HDAC8 cause Cornelia de Lange Syndrome by disrupting active-site geometry and impairing SMC3 deacetylation, and these catalytic defects can be partially rescued by small-molecule HDAC8 activators (PMID:25075551, PMID:26463496). AMPK-mediated phosphorylation drives HDAC8 nuclear-to-cytoplasmic translocation, uncoupling it from histone substrates and derepressing target genes such as PGM1 (PMID:32171858).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 High

    Establishing HDAC8 as a bona fide class I histone deacetylase answered the question of whether additional HDACs with distinct expression patterns existed; mutagenesis of active-site histidines proved these residues are essential for catalysis.

    Evidence Cloning, immunopurified in vitro HDAC assays on H4 peptide/core histones, active-site His mutagenesis

    PMID:10926844

    Open questions at the time
    • Physiological substrates beyond bulk histones unknown
    • In vivo function not addressed
    • Regulatory mechanisms not explored
  2. 2008 Low

    Nuclear localization and interaction with CREB/PP1 suggested HDAC8 could modulate signaling-responsive transcription, expanding its role beyond histone deacetylation.

    Evidence Co-immunoprecipitation and overexpression with luciferase reporter in HEK293 cells

    PMID:19070599

    Open questions at the time
    • Single co-IP without reciprocal validation or endogenous confirmation
    • No direct deacetylation of CREB shown
    • Relevance to physiological signaling unclear
  3. 2014 High

    Identification of SMC3 as the key HDAC8 substrate for cohesin recycling, and structural characterization of Cornelia de Lange Syndrome mutations, established the molecular basis by which HDAC8 loss-of-function causes a developmental disorder.

    Evidence HDAC8 inhibitor/siRNA with ac-SMC3 Western blot and cell cycle analysis; X-ray crystallography of five CdLS mutants with enzymatic and thermostability assays plus activator rescue

    PMID:25075551 PMID:26463496 PMID:27072133

    Open questions at the time
    • Whether CdLS phenotypes are entirely explained by impaired SMC3 deacetylation versus other substrates
    • No patient-derived cell rescue data shown
  4. 2014 Medium

    Discovery that HDAC8 partners with EZH2 to co-repress Wnt antagonists, and with STAT3 to repress BMF, revealed that HDAC8 operates in transcriptional repressor complexes with distinct co-factors at specific promoters.

    Evidence Co-IP and ChIP in HCC and leukemia cells, with RNAi/overexpression functional validation

    PMID:24404147 PMID:25321483 PMID:26383163

    Open questions at the time
    • Genome-wide extent of HDAC8–EZH2 co-occupancy not mapped
    • DEC1 and STAT3 interactions each from single labs
  5. 2017 High

    Demonstration that HDAC8 deacetylates p53 to suppress apoptosis in hematopoietic stem cells, with genetic epistasis rescue by p53 deletion, established a non-histone substrate axis controlling stem cell maintenance.

    Evidence Hdac8 conditional KO mice, serial repopulation assays, co-IP, p53 double KO rescue

    PMID:29084772

    Open questions at the time
    • Specific p53 lysine residue(s) deacetylated by HDAC8 not mapped
    • Whether this axis operates in non-hematopoietic stem cells unknown
  6. 2019 High

    Identification of c-Jun K273 as an HDAC8 deacetylation site driving AP-1 activity and BRAF inhibitor resistance in melanoma demonstrated a direct role for HDAC8 in drug resistance signaling through non-histone substrate modification.

    Evidence MS-based phosphoproteomics, K273 site mutagenesis, in vivo xenograft studies

    PMID:30987999

    Open questions at the time
    • Whether HDAC8 deacetylates additional AP-1 family members
    • Clinical relevance of HDAC8 inhibition in BRAF-resistant melanoma not established
  7. 2020 Medium

    AMPK phosphorylation of HDAC8 was shown to drive its nuclear-to-cytoplasmic translocation under glucose deprivation, establishing a metabolic signaling axis that dynamically regulates HDAC8 chromatin occupancy.

    Evidence AMPK activation/inhibition, nuclear-cytoplasmic fractionation, Western blot in lung cancer cells

    PMID:32171858

    Open questions at the time
    • Specific phosphorylation site on HDAC8 not identified
    • Whether AMPK-mediated translocation alters non-histone substrate deacetylation unknown
    • Single-lab observation
  8. 2020 High

    PKM2 K62 deacetylation by HDAC8 was shown to promote PKM2 nuclear translocation and β-catenin/CCND1 signaling, extending HDAC8's non-histone substrate repertoire to metabolic enzymes with moonlighting transcriptional roles.

    Evidence Co-IP, K62 site-directed mutagenesis, subcellular fractionation, ChIP, enzymatic assays in HCC cells

    PMID:33279948

    Open questions at the time
    • Whether PKM2 deacetylation by HDAC8 occurs in non-cancer contexts
    • Structural basis for HDAC8–PKM2 recognition not defined
  9. 2021 High

    Genome-wide chromatin profiling established HDAC8 as an H3K27-specific deacetylase in HCC, and its interaction with the FACT complex at the MAP2K3 promoter in keratinocytes revealed tissue-specific chromatin complexes maintaining immune tolerance.

    Evidence ChIP-Seq (H3K27ac), selective HDAC8 inhibitor in humanized mouse models; proteomic identification of FACT complex, keratinocyte-specific KO mice

    PMID:33827976 PMID:34021025

    Open questions at the time
    • Whether H3K27 specificity holds across all cell types or is context-dependent
    • Precise mechanism of HDAC8–FACT cooperation at chromatin not structurally resolved
  10. 2023 High

    HDAC8 deacetylation of the acetyltransferase EP300 was shown to inactivate EP300 and redirect its chromatin occupancy, establishing a direct enzymatic crosstalk between a deacetylase and an acetyltransferase that drives melanoma cell-state switching and brain metastasis.

    Evidence Mass spectrometry, ATAC-Seq, ChIP-Seq (H3K27ac), HDAC8 inhibition, in vivo brain metastasis model

    PMID:38030596

    Open questions at the time
    • Specific EP300 lysine(s) deacetylated by HDAC8 not fully mapped
    • Whether EP300 inactivation is a general HDAC8 mechanism or melanoma-specific
  11. 2023 Medium

    PROTAC-mediated degradation of HDAC8 (and HDAC3) showed that loss of these proteins does not globally alter histone acetylation, raising the question of whether HDAC8's primary physiological substrates are non-histone proteins and whether inhibitor-induced hyperacetylation reflects off-target effects.

    Evidence PROTAC-induced degradation, quantitative proteomics, histone acetylation Western blot, RNA-Seq

    PMID:37572669

    Open questions at the time
    • Whether locus-specific histone acetylation changes were missed in bulk analysis
    • Relative contribution of catalytic versus scaffolding functions of HDAC8 not resolved
    • Single-lab observation

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full catalog of physiological HDAC8 substrates, the structural basis for its context-dependent histone versus non-histone substrate selectivity, and how AMPK-mediated translocation integrates with its chromatin and cytoplasmic functions remain unresolved.
  • No systematic in vivo substrate identification (e.g., acetylomics in HDAC8-null cells)
  • No structure of HDAC8 bound to a full-length non-histone substrate
  • Tissue-specific regulatory mechanisms largely uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 6 GO:0042393 histone binding 4 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-5357801 Programmed Cell Death 2
Partners
DEC1EP300EZH2SMC3SSRP1STAT3SUPT16HTP53
Complex memberships
HDAC8–EZH2 repressive complexHDAC8–FACT complex (SSRP1/SUPT16H)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 HDAC8 was cloned and characterized as a new class I HDAC with trichostatin A- and sodium butyrate-inhibitable deacetylase activity on histone H4 peptide substrates and core histones; mutation of two adjacent histidine residues in the predicted active site severely decreased activity, confirming these residues as essential for catalysis. Expression in cell systems, immunopurification, in vitro HDAC activity assay, active-site histidine mutagenesis The Biochemical journal High 10926844
2014 HDAC8 is the Zn2+-dependent SMC3 (cohesin subunit) lysine deacetylase required for cohesin recycling during the cell cycle; HDAC8 inhibition leads to accumulation of acetylated SMC3, delays cell cycle progression, and suppresses proliferation without affecting cohesin-dependent transcription of estrogen-responsive genes. HDAC8-specific inhibitor (PCI-34051), Western blot for ac-SMC3, ChIP, siRNA knockdown, cell cycle analysis The Journal of biological chemistry High 27072133
2014 HDAC8 physically interacts with EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3K27 trimethylation in NAFLD-associated hepatocellular carcinoma cells. Co-immunoprecipitation, ChIP, lentiviral knockdown in vivo, Western blot Cancer research Medium 26383163
2014 HDAC8 and STAT3 directly repress the BMF gene promoter; HDAC8 occupancy at the BMF promoter was identified as a direct transcriptional target, and overexpression of HDAC8 interfered with BMF induction whereas HDAC8 RNAi activated it. ChIP, RNAi knockdown, transient overexpression, p300 inhibitor treatment, reporter assay Cell death & disease Medium 25321483
2014 X-ray crystal structures of five CdLS-associated HDAC8 missense mutants (C153F, A188T, I243N, T311M, H334R) revealed local structural changes that compromise catalysis and/or thermostability; the catalytic activity of these mutants could be partially or fully rescued in vitro by the HDAC8 activator N-(phenylcarbamothioyl)benzamide. X-ray crystallography, enzymatic activity assays, thermostability assays, activator rescue experiments ACS chemical biology High 25075551
2015 X-ray crystal structures of additional CdLS HDAC8 mutants (G117E, P91L-Y306F, D233G-Y306F) showed that CdLS mutations disrupt key hydrogen bond networks and active-site residue positioning, compromising catalysis and thermostability; molecular dynamics simulations of H180R and G304R showed bulky arginine side chains protruding into the substrate binding site. X-ray crystallography, molecular dynamics simulations, enzymatic activity assays, thermostability assays Biochemistry High 26463496
2016 Structure-based identification of novel HDAC8 non-histone substrates using Rosetta FlexPepBind revealed that SMC3, ERRα, and ARID1A are among known non-histone HDAC8 substrates, and the in silico approach identified many additional acetyl-lysine-containing peptides as HDAC8 substrates in vitro. Structure-based computational docking (Rosetta FlexPepBind), in vitro peptide deacetylation assays Structure Medium 26933971
2017 HDAC8 protein interacts with p53 and modulates p53 activity via deacetylation; HDAC8-deficient LT-HSCs displayed hyperactivation of p53, increased apoptosis under stress, and compromised long-term repopulating activity, all of which were rescued by genetic inactivation of p53. Co-immunoprecipitation, Hdac8 conditional knockout, serial repopulation assays, genetic epistasis (p53 double KO), Western blot Blood High 29084772
2019 HDAC8 deacetylates c-Jun at lysine 273, decreasing c-Jun acetylation and increasing its transcriptional activity; HDAC8-mediated BRAF inhibitor resistance in melanoma is mediated through receptor tyrosine kinase activation and MAPK/AP-1 signaling. Mass spectrometry-based phosphoproteomics, HDAC8 introduction into drug-naïve cells, in vitro and in vivo xenograft studies, c-Jun K273 acetylation site mutagenesis Cancer research High 30987999
2019 HDAC8 interacts with the proteasome receptor ADRM1 to regulate MGMT protein levels independent of MGMT promoter methylation in glioblastoma cells; HDAC8 inhibition or shRNA decreased MGMT levels and increased DNA damage and cell cycle arrest. Co-immunoprecipitation, HDAC8-specific inhibitor (PCI34051), shRNA knockdown, Western blot Genes & cancer Medium 31798765
2019 HDAC8 binds the ID2 enhancer and represses ID2 transcription; lncRNA ID2-AS1 suppresses HCC metastasis by blocking HDAC8 binding to the ID2 enhancer, thereby increasing H3K27 acetylation and ID2 expression. ChIP, RNAi knockdown, overexpression, migration/invasion assays in vitro and in vivo Cancer letters Medium 31730902
2020 FLT3 inhibition induces HDAC8 upregulation through FOXO1- and FOXO3-mediated transactivation; upregulated HDAC8 deacetylates and inactivates p53, promoting FLT3-ITD+ AML maintenance and TKI resistance. Genetic/pharmacological HDAC8 inhibition, FOXO1/3 ChIP, p53 acetylation Western blot, patient-derived xenograft models Blood High 32315388
2020 AMPK phosphorylates HDAC8 in response to glucose deprivation, stimulating HDAC8 translocation from the nucleus to the cytoplasm and disrupting HDAC8 binding to histone H3, thereby derepressing PGM1 expression in lung cancer cells. Co-immunoprecipitation, nuclear/cytoplasmic fractionation, Western blot, AMPK inhibition/activation Cancer letters Medium 32171858
2020 HDAC8 binds and deacetylates PKM2 at the K62 residue; K62 deacetylation facilitates PKM2 nuclear translocation where it binds β-catenin to promote CCND1 transcription and cell cycle progression in hepatocellular carcinoma. Co-immunoprecipitation, site-directed mutagenesis (K62), subcellular fractionation, ChIP, enzymatic activity assays Cell death & disease High 33279948
2021 HDAC8 is an H3K27-specific deacetylase in HCC; pharmacological inhibition of HDAC8 increases global and enhancer H3K27 acetylation, reactivating T cell-trafficking chemokines and relieving T cell exclusion. Chromatin profiling (ChIP-Seq), selective HDAC8 inhibitor treatment, humanized and immunodeficient mouse models Science translational medicine High 33827976
2021 HDAC8 interacts with HDAC9 and the FACT complex (SSRP1 and SUPT16H) to regulate H3K9 and H3K27 acetylation at the MAP2K3 promoter, thereby suppressing MAP2K3 expression and maintaining cutaneous innate immune tolerance in keratinocytes. Proteomic analysis (HDAC8/9 interactors), ChIP for histone marks, HDAC8/9 siRNA, keratinocyte-specific KO mice, cytokine assays Science immunology High 34021025
2018 HDAC8 associates with α-smooth muscle actin (α-SMA) in TGFβ1-treated lung fibroblasts as shown by co-immunoprecipitation; HDAC8 inhibition represses TGFβ1-induced fibroblast contraction, α-SMA expression, and fibrotic gene expression, and increases H3K27ac at the PPARγ gene enhancer. Co-immunoprecipitation, HDAC8-selective inhibitor (NCC170), siRNA knockdown, ChIP-qPCR (H3K27ac), collagen gel contraction assay, bleomycin mouse model American journal of physiology. Lung cellular and molecular physiology High 30358439
2014 DEC1 interacts with HDAC8 and recruits HDAC8 to the TAp73 promoter to enhance TAp73 expression; HDAC8 is required for DEC1-mediated transcriptional activation of TAp73 but not ΔNp73. Co-immunoprecipitation, ChIP, RNAi knockdown, reporter assay PloS one Medium 24404147
2008 HDAC8 localizes in the nucleus of HEK293 cells and binds both CREB and PP1; expression of HDAC8 decreases CREB phosphorylation at S133 and CREB-mediated gene transcription in response to forskolin. Co-immunoprecipitation, subcellular localization, overexpression, luciferase reporter assay Biochemical and biophysical research communications Low 19070599
2016 HDAC8 maintains Notch1 protein stability in breast cancer cells through a non-epigenetic mechanism; HDAC8 inhibition promotes Notch1 proteasomal degradation via Fbxw7, although HDAC8 does not form a complex with Notch1 and inhibition does not affect Notch1 acetylation. Co-immunoprecipitation, siRNA/shRNA knockdown, proteasome inhibitor (MG132), Fbxw7 siRNA, xenograft model Oncotarget Medium 26625202
2023 HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation; increased HDAC8 activity leads to EP300 binding at c-Jun transcriptional sites (increasing chromatin accessibility) and away from MITF sites, driving a neural crest-stem cell state that promotes melanoma brain metastasis. ATAC-Seq, ChIP-Seq (H3K27ac), mass spectrometry, HDAC8 inhibition, in vivo brain metastasis model Nature communications High 38030596
2023 Simultaneous PROTAC-mediated degradation of HDAC3 and HDAC8 (YX968) does not induce global histone hyperacetylation or broad transcriptomic perturbation, suggesting that histone hyperacetylation is a major factor driving transcriptional changes induced by HDAC inhibitors rather than loss of HDAC3/8 catalytic activity per se. PROTAC-induced protein degradation, quantitative proteomics, histone acetylation Western blot, RNA-Seq, cell viability assays Cell chemical biology Medium 37572669
2021 HDAC8 inhibition in cardiac hypertrophy promotes p38 MAPK dephosphorylation; HDAC8 overexpression promoted p38 MAPK phosphorylation and cardiac hypertrophic marker expression, while HDAC8 knockdown or selective inhibition (PCI34051) reversed isoproterenol-induced hypertrophy via reduction of p38 MAPK activity. HDAC8 selective inhibitor (PCI34051), HDAC8 knockdown/overexpression, Western blot (p38 MAPK phosphorylation), mouse isoproterenol model, echocardiography Frontiers in pharmacology Medium 33959033
2020 HDAC8 interacts with galectin-3 (Gal-3) as shown by co-immunoprecipitation; selective HDAC8 inhibition (PCI-34051) synchronously reduces HDAC8-Gal-3 complex levels and M2 macrophage polarization, attenuating airway hyperresponsiveness. Co-immunoprecipitation, immunofluorescence, selective inhibitor (PCI-34051), shRNA knockdown Respiratory research Low 32111211

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nature reviews. Molecular cell biology 986 18292778
2005 Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell 653 16286008
1996 HDA1 and RPD3 are members of distinct yeast histone deacetylase complexes that regulate silencing and transcription. Proceedings of the National Academy of Sciences of the United States of America 546 8962081
1997 Repression by Ume6 involves recruitment of a complex containing Sin3 corepressor and Rpd3 histone deacetylase to target promoters. Cell 488 9150136
1998 Transcriptional repression by UME6 involves deacetylation of lysine 5 of histone H4 by RPD3. Nature 369 9572144
1999 A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes & development 348 10485845
1998 Characterization of a human RPD3 ortholog, HDAC3. Proceedings of the National Academy of Sciences of the United States of America 277 9501169
1991 RPD3 encodes a second factor required to achieve maximum positive and negative transcriptional states in Saccharomyces cerevisiae. Molecular and cellular biology 264 1944291
2004 The MAPK Hog1 recruits Rpd3 histone deacetylase to activate osmoresponsive genes. Nature 256 14737171
2002 Genome-wide binding map of the histone deacetylase Rpd3 in yeast. Nature genetics 236 12089521
1998 Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo. Genes & development 202 9512514
1996 The histone deacetylase RPD3 counteracts genomic silencing in Drosophila and yeast. Nature 198 8955276
2001 Widespread collaboration of Isw2 and Sin3-Rpd3 chromatin remodeling complexes in transcriptional repression. Molecular and cellular biology 168 11533234
2004 The Rpd3-Sin3 histone deacetylase regulates replication timing and enables intra-S origin control in Saccharomyces cerevisiae. Molecular and cellular biology 141 15143171
2009 Histone chaperones ASF1 and NAP1 differentially modulate removal of active histone marks by LID-RPD3 complexes during NOTCH silencing. Molecular cell 135 19782028
2000 Cloning and characterization of a novel human histone deacetylase, HDAC8. The Biochemical journal 135 10926844
2021 A selective HDAC8 inhibitor potentiates antitumor immunity and efficacy of immune checkpoint blockade in hepatocellular carcinoma. Science translational medicine 132 33827976
2002 RPD3 is required for the inactivation of yeast ribosomal DNA genes in stationary phase. The EMBO journal 111 12234935
2015 Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma. Cancer research 110 26383163
2009 Genome-wide replication profiles indicate an expansive role for Rpd3L in regulating replication initiation timing or efficiency, and reveal genomic loci of Rpd3 function in Saccharomyces cerevisiae. Genes & development 108 19417103
2003 A 1-megadalton ESC/E(Z) complex from Drosophila that contains polycomblike and RPD3. Molecular and cellular biology 107 12697833
2001 The histone deacetylase genes HDA1 and RPD3 play distinct roles in regulation of high-frequency phenotypic switching in Candida albicans. Journal of bacteriology 102 11443097
2000 Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase. The EMBO journal 100 10899127
2012 Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance. Cell reports 95 23041319
1999 A general requirement for the Sin3-Rpd3 histone deacetylase complex in regulating silencing in Saccharomyces cerevisiae. Genetics 94 10388812
2016 Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis. Journal of medicinal chemistry 90 26937828
2018 Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview. European journal of medicinal chemistry 81 30594678
2007 Histone deacetylases RPD3 and HOS2 regulate the transcriptional activation of DNA damage-inducible genes. Molecular and cellular biology 80 17296735
2000 Functional analysis of a RPD3 histone deacetylase homologue in Arabidopsis thaliana. Plant molecular biology 79 11117260
2014 The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast. Molecular cell 77 24856221
2009 Phylogenetic analysis, subcellular localization, and expression patterns of RPD3/HDA1 family histone deacetylases in plants. BMC plant biology 72 19327164
2013 HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity. Kidney & blood pressure research 70 23868068
2005 Drosophila Mob family proteins interact with the related tricornered (Trc) and warts (Wts) kinases. Molecular biology of the cell 69 15975907
2017 Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity. Journal of medicinal chemistry 68 29190092
2014 HDAC8 and STAT3 repress BMF gene activity in colon cancer cells. Cell death & disease 68 25321483
2009 Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert opinion on investigational drugs 67 19780707
2020 FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia. Blood 64 32315388
2009 The E2F functional analogue SBF recruits the Rpd3(L) HDAC, via Whi5 and Stb1, and the FACT chromatin reorganizer, to yeast G1 cyclin promoters. The EMBO journal 64 19745812
2008 The H3K4 demethylase lid associates with and inhibits histone deacetylase Rpd3. Molecular and cellular biology 63 19114561
2002 The SIN3/RPD3 deacetylase complex is essential for G(2) phase cell cycle progression and regulation of SMRTER corepressor levels. Molecular and cellular biology 63 12077326
2019 LncRNA ID2-AS1 suppresses tumor metastasis by activating the HDAC8/ID2 pathway in hepatocellular carcinoma. Cancer letters 60 31730902
2020 AMPK-dependent phosphorylation of HDAC8 triggers PGM1 expression to promote lung cancer cell survival under glucose starvation. Cancer letters 57 32171858
2022 Pathological Role of HDAC8: Cancer and Beyond. Cells 56 36231123
2019 HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy. Cancer research 56 30987999
2008 Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase. Biochemical and biophysical research communications 55 19070599
2019 MiR-216b-5p inhibits cell proliferation in human breast cancer by down-regulating HDAC8 expression. Life sciences 54 31605710
1999 GCN5-dependent histone H3 acetylation and RPD3-dependent histone H4 deacetylation have distinct, opposing effects on IME2 transcription, during meiosis and during vegetative growth, in budding yeast. Proceedings of the National Academy of Sciences of the United States of America 54 10359799
2021 Selective HDAC8 Inhibition Attenuates Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis via p38 MAPK Pathway. Frontiers in pharmacology 53 33959033
2018 HDAC8 inhibition ameliorates pulmonary fibrosis. American journal of physiology. Lung cellular and molecular physiology 52 30358439
2020 HDAC8-dependent deacetylation of PKM2 directs nuclear localization and glycolysis to promote proliferation in hepatocellular carcinoma. Cell death & disease 51 33279948
2014 Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders. ACS chemical biology 51 25075551
2016 HDAC8 Inhibition Blocks SMC3 Deacetylation and Delays Cell Cycle Progression without Affecting Cohesin-dependent Transcription in MCF7 Cancer Cells. The Journal of biological chemistry 50 27072133
2003 Loss of Sin3/Rpd3 histone deacetylase restores the DNA damage response in checkpoint-deficient strains of Saccharomyces cerevisiae. Molecular and cellular biology 50 12808094
2009 Histone deacetylase Rpd3 antagonizes Sir2-dependent silent chromatin propagation. Nucleic acids research 49 19372273
2017 HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity. Blood 46 29084772
2002 Targeted recruitment of Rpd3 histone deacetylase represses transcription by inhibiting recruitment of Swi/Snf, SAGA, and TATA binding protein. Molecular and cellular biology 45 12192044
1998 Identification and characterisation of an RPD3 homologue from maize (Zea mays L.) that is able to complement an rpd3 null mutant of Saccharomyces cerevisiae. Molecular & general genetics : MGG 45 9645435
2016 Structure-Based Identification of HDAC8 Non-histone Substrates. Structure (London, England : 1993) 42 26933971
2021 Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9. Science immunology 40 34021025
2020 Hydroxamic acid derivatives as HDAC1, HDAC6 and HDAC8 inhibitors with antiproliferative activity in cancer cell lines. Scientific reports 40 32591593
2015 Biochemical and structural characterization of HDAC8 mutants associated with Cornelia de Lange syndrome spectrum disorders. Biochemistry 36 26463496
2007 Direct role for the Rpd3 complex in transcriptional induction of the anaerobic DAN/TIR genes in yeast. Molecular and cellular biology 36 17210643
2018 Essential role of Rpd3-dependent lysine modification in the growth, development and virulence of Beauveria bassiana. Environmental microbiology 35 29575704
2024 Butyrate Inhibits the HDAC8/NF-κB Pathway to Enhance Slc26a3 Expression and Improve the Intestinal Epithelial Barrier to Relieve Colitis. Journal of agricultural and food chemistry 34 39440960
2020 Characterization of Conformationally Constrained Benzanilide Scaffolds for Potent and Selective HDAC8 Targeting. Journal of medicinal chemistry 34 32672458
2019 Discovery of 5-naphthylidene-2,4-thiazolidinedione derivatives as selective HDAC8 inhibitors and evaluation of their cytotoxic effects in leukemic cell lines. Bioorganic chemistry 34 31901516
2008 Different genetic functions for the Rpd3(L) and Rpd3(S) complexes suggest competition between NuA4 and Rpd3(S). Molecular and cellular biology 34 18490440
2004 The unfolded protein response represses differentiation through the RPD3-SIN3 histone deacetylase. The EMBO journal 34 15141165
2022 Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity. International journal of molecular sciences 33 35886887
2019 HDAC8 affects MGMT levels in glioblastoma cell lines via interaction with the proteasome receptor ADRM1. Genes & cancer 33 31798765
2018 Structure-activity relationships of HDAC8 inhibitors: Non-hydroxamates as anticancer agents. Pharmacological research 33 29514055
2004 Cti6 is an Rpd3-Sin3 histone deacetylase-associated protein required for growth under iron-limiting conditions in Saccharomyces cerevisiae. The Journal of biological chemistry 33 15133041
2023 HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation. Cell chemical biology 32 37572669
2016 Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders. Protein science : a publication of the Protein Society 32 27576763
2014 DEC1 coordinates with HDAC8 to differentially regulate TAp73 and ΔNp73 expression. PloS one 32 24404147
2014 Transcriptional regulation of ATG9 by the Pho23-Rpd3 complex modulates the frequency of autophagosome formation. Autophagy 32 25046109
2010 Histone deacetylase Rpd3 regulates olfactory projection neuron dendrite targeting via the transcription factor Prospero. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 20660276
2021 Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research 31 33542077
2021 NBM-BMX, an HDAC8 Inhibitor, Overcomes Temozolomide Resistance in Glioblastoma Multiforme by Downregulating the β-Catenin/c-Myc/SOX2 Pathway and Upregulating p53-Mediated MGMT Inhibition. International journal of molecular sciences 31 34072831
2020 Opposing functions of Fng1 and the Rpd3 HDAC complex in H4 acetylation in Fusarium graminearum. PLoS genetics 31 33137093
2009 Collaboration between the essential Esa1 acetyltransferase and the Rpd3 deacetylase is mediated by H4K12 histone acetylation in Saccharomyces cerevisiae. Genetics 31 19596907
2006 Role of histone deacetylase Rpd3 in regulating rRNA gene transcription and nucleolar structure in yeast. Molecular and cellular biology 31 16648483
2020 Cholesterol derivatives induce dephosphorylation of the histone deacetylases Rpd3/HDAC1 to upregulate autophagy. Autophagy 30 32013726
2017 An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division. Developmental cell 30 28245922
2011 Genetic modulation of Rpd3 expression impairs long-term courtship memory in Drosophila. PloS one 30 22195015
2020 Discovery of novel N-substituted thiazolidinediones (TZDs) as HDAC8 inhibitors: in-silico studies, synthesis, and biological evaluation. Bioorganic chemistry 29 32446120
2020 The Mi-2 nucleosome remodeler and the Rpd3 histone deacetylase are involved in piRNA-guided heterochromatin formation. Nature communications 28 32499524
2018 Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors. European journal of medicinal chemistry 28 29533873
2000 In Saccharomyces cerevisiae, expression of arginine catabolic genes CAR1 and CAR2 in response to exogenous nitrogen availability is mediated by the Ume6 (CargRI)-Sin3 (CargRII)-Rpd3 (CargRIII) complex. Journal of bacteriology 28 10809695
2022 HDAC8 suppresses the epithelial phenotype and promotes EMT in chemotherapy-treated basal-like breast cancer. Clinical epigenetics 27 35016723
2013 Synthesis and biological evaluation of a targeted DNA-binding transcriptional activator with HDAC8 inhibitory activity. Bioorganic & medicinal chemistry 27 23719282
1990 High frequency expression of S107 VH genes by peritoneal B cells of B10.H-2aH-4bP/WTS mice. Journal of immunology (Baltimore, Md. : 1950) 27 2117034
2023 Discovery of highly potent HDAC8 PROTACs with anti-tumor activity. Bioorganic chemistry 26 37098288
2022 Long noncoding RNA LINC01435 impedes diabetic wound healing by facilitating YY1-mediated HDAC8 expression. iScience 26 35330681
2020 HDAC8 inhibitor attenuates airway responses to antigen stimulus through synchronously suppressing galectin-3 expression and reducing macrophage-2 polarization. Respiratory research 25 32111211
2019 Design, synthesis, biological evaluation and molecular docking study of arylcarboxamido piperidine and piperazine-based hydroxamates as potential HDAC8 inhibitors with promising anticancer activity. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 25 31421254
2023 HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis. Nature communications 24 38030596
2016 Non-epigenetic function of HDAC8 in regulating breast cancer stem cells by maintaining Notch1 protein stability. Oncotarget 24 26625202
2023 Are inhibitors of histone deacetylase 8 (HDAC8) effective in hematological cancers especially acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)? European journal of medicinal chemistry 23 37429084
2019 Selective and nonselective HDAC8 inhibitors: a therapeutic patent review. Pharmaceutical patent analyst 23 30632447