Affinage

SMYD3

Histone-lysine N-methyltransferase SMYD3 · UniProt Q9H7B4

Length
428 aa
Mass
49.1 kDa
Annotated
2026-04-28
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMYD3 is a SET-domain lysine methyltransferase that functions both as a chromatin modifier and a cytoplasmic signaling regulator, coupling histone methylation-dependent transcriptional control to post-translational modification of non-histone substrates in kinase and DNA-damage-response pathways. In the nucleus, SMYD3 catalyzes H3K4, H4K5, H4K20, and H2A.Z.1-K101 methylation at target gene promoters, cooperating with cofactors including ERα, BRD4, PC4/SUB1, and SMAD3 to activate transcription of cell-cycle, EMT, and immune-regulatory genes (PMID:15235609, PMID:22419068, PMID:27569210, PMID:23752591, PMID:26350217, PMID:30544196, PMID:37463106). In the cytoplasm, SMYD3 methylates MAP3K2 at K260 to block PP2A binding and potentiate Ras-ERK signaling, methylates AKT1 at K14 to promote its membrane recruitment, trimethylates HER2-K175 to enhance homodimerization, and methylates RNF113A to regulate its E3 ligase activity in the alkylation damage response (PMID:24847881, PMID:27626683, PMID:28639750, PMID:35819319). Its enzymatic activity is stimulated by HSP90α binding to a C-terminal TPR-like domain and by DNA binding, and ATM-dependent phosphorylation recruits SMYD3 into a BRCA2–CHK2 complex required for RAD51 loading during homologous recombination (PMID:15235609, PMID:25738358, PMID:21266482, PMID:33205017).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    The foundational question of SMYD3's enzymatic identity was resolved: it is an H3K4-specific methyltransferase whose activity is enhanced by HSP90A, and it associates with RNA Pol II via HELZ to transactivate target genes, establishing it as a transcription-coupled chromatin modifier.

    Evidence In vitro methyltransferase assay, Co-IP, promoter binding assay, and siRNA knockdown in cancer cell lines

    PMID:15235609

    Open questions at the time
    • HSP90A stimulation mechanism not structurally resolved
    • direct versus indirect nature of RNA Pol II association unclear
    • full substrate specificity unknown
  2. 2007 Medium

    SMYD3 was shown to methylate the non-histone substrate VEGFR1 at K831, extending its activity beyond chromatin and suggesting it regulates receptor tyrosine kinase signaling; separately, N-terminal processing and HSP90α interaction were shown to modulate enzymatic output.

    Evidence In vitro methyltransferase assay with mass spectrometry site identification; N-terminal sequencing and mutagenesis with Co-IP

    PMID:17998933 PMID:18006819

    Open questions at the time
    • VEGFR1 methylation not validated in vivo
    • physiological relevance of N-terminal cleavage unclear
    • structural basis for HSP90-mediated activation unknown
  3. 2009 Medium

    SMYD3 was established as a nuclear coactivator of estrogen receptor α, linking its H3K4 methyltransferase activity to hormone-regulated transcription programs.

    Evidence Co-IP of SMYD3–ERα, ChIP at ER target genes, siRNA knockdown with transcriptional readout

    PMID:19509295

    Open questions at the time
    • whether SMYD3 methylates ERα directly not tested
    • contribution relative to other H3K4 methyltransferases at ER targets undetermined
  4. 2011 High

    The crystal structure of full-length SMYD3 revealed how the C-terminal TPR domain, SET domain, and post-SET domain cooperate to form the substrate binding cleft, and identified Tyr239 as catalytically essential; DNA binding through the MYND domain was shown to stimulate methyltransferase activity.

    Evidence 2.8 Å X-ray crystallography, active-site mutagenesis, in vitro histone methyltransferase and DNA-binding assays

    PMID:21266482

    Open questions at the time
    • no co-crystal with histone peptide substrate
    • how DNA binding allosterically activates catalysis not resolved
  5. 2012 High

    H4K5 was identified as an additional histone substrate, broadening SMYD3's chromatin-modifying repertoire beyond H3K4 and linking its enzymatic activity to cancer cell phenotypes.

    Evidence In vitro methyltransferase assay with mass spectrometry, siRNA knockdown with H4K5me detection

    PMID:22419068

    Open questions at the time
    • genomic distribution of SMYD3-dependent H4K5me not mapped
    • whether H4K5me is functionally distinct from H3K4me at SMYD3 targets unknown
  6. 2013 High

    The mechanism of SMYD3-driven transcriptional elongation was elucidated: SMYD3 recruits BRD4 and the p-TEFb pause-release factor to gene regulatory regions, promoting Ser2-phosphorylated Pol II elongation, with in vivo relevance in glucocorticoid-induced muscle atrophy.

    Evidence Co-IP of SMYD3–BRD4, ChIP for elongation marks, shRNA knockdown, mouse dexamethasone-atrophy model

    PMID:23752591

    Open questions at the time
    • whether SMYD3 methylates BRD4 directly not tested
    • precise recruitment order of SMYD3 versus BRD4 undetermined
  7. 2014 High

    A major cytoplasmic function was defined: SMYD3 methylates MAP3K2 at K260 to block PP2A binding, amplifying Ras-ERK signaling and driving Ras-dependent tumorigenesis — establishing SMYD3 as a bona fide oncogenic signaling regulator outside the nucleus.

    Evidence Protein array substrate screen, in vitro methyltransferase assay, Co-IP, KRAS-driven mouse pancreatic and lung cancer models, catalytic mutant and MEK inhibitor epistasis

    PMID:24847881

    Open questions at the time
    • whether additional MAP kinase pathway kinases are SMYD3 substrates unknown
    • signals governing SMYD3 nuclear versus cytoplasmic partitioning not defined
  8. 2015 Medium

    The HSP90–TPR domain interaction was mapped as essential for SMYD3 chromatin association and basal enzymatic activity; separately, the transcriptional coactivator PC4 was identified as a co-dependent partner for SMYD3-mediated H3K4me3 at target genes.

    Evidence Domain deletion/mutagenesis with Co-IP and subcellular fractionation; Co-IP and ChIP for PC4–SMYD3 co-occupancy

    PMID:25738358 PMID:26350217

    Open questions at the time
    • whether HSP90 acts as an allosteric activator or a folding chaperone for SMYD3 not distinguished
    • PC4 interaction not confirmed by independent group
  9. 2016 High

    Multiple advances converged: structural co-crystals with MAP3K2 and VEGFR1 peptides explained substrate preference determinants; H2A.Z.1-K101 methylation was discovered to stabilize H2A.Z.1 at promoters driving cell cycle progression; SMYD3 was found to read H3K4me3 and recruit Pol II genome-wide; and AKT1-K14 methylation was linked to AKT membrane localization.

    Evidence Co-crystallography with kinetic validation; in vitro methyltransferase assays; ChIP-seq and Smyd3-knockout mice in chemical carcinogenesis; subcellular fractionation of methylated AKT1

    PMID:26908355 PMID:26929412 PMID:27066749 PMID:27569210 PMID:27626683

    Open questions at the time
    • physiological significance of AKT1-K14 methylation confirmed only in cell lines
    • relative contribution of SMYD3's histone versus non-histone activities to tumorigenesis not separated in vivo
  10. 2017 Medium

    SMYD3 was shown to trimethylate HER2-K175, promoting receptor homodimerization and autophosphorylation, adding another receptor tyrosine kinase to its non-histone substrate portfolio.

    Evidence In vitro methyltransferase assay, K175A mutagenesis reducing dimerization, siRNA knockdown in breast cancer cells

    PMID:28639750

    Open questions at the time
    • HER2 methylation not validated in vivo
    • structural basis for how K175 methylation promotes dimerization unknown
  11. 2019 Medium

    Three new functional axes were defined: SMYD3 facilitates SMAD3 chromatin binding during TGFβ-driven EMT; promotes p53 cytoplasmic translocation and MDM2-independent ubiquitination via UBE2R2; and is recruited by Ebola virus NP to enhance viral mRNA transcription.

    Evidence Co-IP and ChIP for SMAD3 with SMYD3 inhibitor; Co-IP of SMYD3–p53–UBE2R2 with ubiquitination assay; MS-identified NP–SMYD3 interaction with minigenome system

    PMID:30544196 PMID:31002112 PMID:31516086

    Open questions at the time
    • p53 ubiquitination mechanism (E3 ligase vs. scaffolding) not clarified
    • SMYD3-dependent SMAD3 chromatin binding mechanism unresolved
    • EBOV finding from single system without in vivo confirmation
  12. 2020 Medium

    ATM phosphorylation of SMYD3 was shown to nucleate a BRCA2–CHK2 complex essential for RAD51 loading and homologous recombination, placing SMYD3 in the DNA damage response and rationalizing PARP-inhibitor synergy; separately, SMYD3 nuclear-cytoplasmic shuttling was found to be regulated by cell geometry and actomyosin tension.

    Evidence Co-IP with ATM phospho-mutant SMYD3, RAD51 foci assay, PARP inhibitor sensitization; live-cell imaging of SMYD3 in micropatterned cells with cytoskeletal drugs

    PMID:33205017 PMID:33244033

    Open questions at the time
    • ATM phosphorylation sites on SMYD3 not identified
    • whether SMYD3 methyltransferase activity is required for HR function not fully resolved
    • mechanotransduction pathway linking cytoskeleton to SMYD3 import unknown
  13. 2021 Medium

    SMYD3-mediated H3K4me3 at the Cdkn1a/p21 promoter was identified as a driver of endothelial senescence, with Smyd3-knockout mice protected from angiotensin II-induced vascular aging.

    Evidence ChIP, Smyd3-KO mouse with angiotensin II challenge, siRNA/overexpression, inhibitor treatment

    PMID:32779886

    Open questions at the time
    • whether SMYD3's senescence role extends beyond endothelial cells not tested
    • downstream mediators beyond p21 not characterized
  14. 2022 High

    Two new non-enzymatic and enzymatic functions emerged: SMYD3 methylates RNF113A to regulate its E3 ligase activity in alkylation damage repair (conferring chemotherapy resistance in SCLC); and SMYD3 stabilizes HIF1α protein independently of its methyltransferase activity, promoting hypoxia responses.

    Evidence In vitro methyltransferase assay for RNF113A with PP4 binding and ubiquitin ligase assays, SMYD3 inhibitor in SCLC cells; Co-IP with catalytically dead SMYD3 mutant, zebrafish knockout for HIF1α stability

    PMID:35819319 PMID:36273580

    Open questions at the time
    • RNF113A methylation site(s) not structurally characterized
    • mechanism of methylation-independent HIF1α stabilization not defined
    • whether HIF1α stabilization and RNF113A methylation occur in same cell types unknown
  15. 2023 Medium

    SMYD3's role in immune evasion was delineated: it deposits H4K20me3 at immune gene loci and transcriptionally activates UHRF1/DNMT1-mediated silencing, suppressing type I interferon signaling; SMYD3 depletion restores immune gene expression and sensitizes tumors to anti-PD-1 therapy. In parallel, SMYD3–MAP3K2 signaling was confirmed to sustain EMT in prostate cancer via a positive feedback loop, and SMYD3-dependent H3K4me3 at Fbxo2 was linked to NMDAR degradation in tauopathy models.

    Evidence ChIP-seq for H4K20me3 and SMYD3, in vivo anti-PD-1 mouse tumor model; catalytic mutant SMYD3 with xenografts; ChIP and electrophysiology in P301S tau mice

    PMID:36609445 PMID:37463106 PMID:37976356

    Open questions at the time
    • direct versus indirect deposition of H4K20me3 by SMYD3 at immune loci not fully established
    • Fbxo2 mechanism requires independent replication
    • whether SMYD3–MAP3K2 feedback operates in non-prostate contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the signals and mechanisms controlling SMYD3 nuclear-cytoplasmic partitioning; the relative in vivo contributions of its histone versus non-histone methyltransferase activities to its oncogenic functions; whether the reported E3 ubiquitin ligase-like activity toward p53 reflects a direct catalytic role; and the structural basis for methylation-independent protein stabilization functions.
  • no reconstituted system separating nuclear from cytoplasmic SMYD3 functions in vivo
  • p53 ubiquitination mechanism unresolved
  • no structural basis for HIF1α stabilization

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 12 GO:0140110 transcription regulator activity 11 GO:0042393 histone binding 4 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 8 GO:0005829 cytosol 4 GO:0005694 chromosome 3
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-162582 Signal Transduction 5 R-HSA-4839726 Chromatin organization 5 R-HSA-1643685 Disease 4 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1
Partners
BRCA2BRD4ESR1HSP90AA1MAP3K2RNF113ASMAD3SUB1
Complex memberships
ATM–SMYD3–CHK2–BRCA2 complexSMYD3–HSP90α complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 SMYD3 SET domain possesses histone H3-lysine 4 (H3K4)-specific methyltransferase activity, which is enhanced by heat-shock protein HSP90A; SMYD3 forms a complex with RNA polymerase II through interaction with the RNA helicase HELZ and binds to a 5'-CCCTCC-3' promoter motif to transactivate downstream genes. In vitro methyltransferase assay, Co-immunoprecipitation, promoter binding assay, siRNA knockdown with proliferation readout Nature cell biology High 15235609
2014 SMYD3 methylates MAP3K2 (MEKK2) at lysine 260, potentiating Ras/Raf/MEK/ERK signaling; methylation of MAP3K2 blocks binding of the PP2A phosphatase complex (a negative regulator of the MAP kinase pathway), thereby increasing ERK activation and promoting Ras-driven pancreatic and lung carcinomas. Protein array substrate identification, in vitro methyltransferase assay, Co-IP, mouse cancer models (KRAS-driven pancreatic and lung adenocarcinoma), catalytic mutant SMYD3, MEK inhibitor synergy Nature High 24847881
2007 SMYD3 methylates vascular endothelial growth factor receptor 1 (VEGFR1) at lysine 831 in its kinase domain, and this methylation enhances VEGFR1 kinase activity in cells. In vitro methyltransferase assay, mass spectrometry identification of methylated residue, cell-based kinase activity assay Cancer research Medium 18006819
2012 SMYD3 catalyzes mono- and di-methylation of histone H4 at lysine 5 (H4K5me), a mark detectable in diverse cell types whose formation is attenuated by SMYD3 depletion; SMYD3-driven cancer cell phenotypes require its enzymatic activity. In vitro methyltransferase assay, mass spectrometry, siRNA knockdown with H4K5me detection, cell phenotype assays Epigenetics High 22419068
2011 Crystal structure of full-length human SMYD3 in complex with S-adenosyl-L-homocysteine at 2.8 Å resolution revealed a C-terminal tetratricopeptide repeat (TPR) domain that together with the SET and post-SET domains forms the substrate binding pocket; Tyr239 hydroxyl group is critical for enzymatic activity; DNA binding stimulates SMYD3 histone methyltransferase activity, possibly mediated via the MYND domain. X-ray crystallography, mutagenesis of active site residues, in vitro histone methyltransferase assay, DNA binding biochemical assay Nucleic acids research High 21266482
2007 Cleavage of the N-terminal 34 amino acids of SMYD3 in cancer cells produces a form with higher histone methyltransferase activity; substitution of conserved glycines 15 and 17 also enhances activity; the N-terminal region mediates association with HSP90α, whose binding modulates enzymatic activity. Protein biochemistry, N-terminal sequencing, site-directed mutagenesis, in vitro methyltransferase assay, Co-immunoprecipitation with HSP90α Oncogene Medium 17998933
2009 SMYD3 functions as a coactivator of estrogen receptor alpha (ERα) by directly interacting with the ERα ligand-binding domain; upon estrogen induction, SMYD3 is recruited to ER target gene promoters and is responsible for accumulation of H3K4me2/3, which is required for ER-regulated gene transcription. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown with gene expression readout, domain mapping The Journal of biological chemistry Medium 19509295
2013 SMYD3 recruits the bromodomain protein BRD4 to myostatin and c-Met gene regulatory regions through protein-protein interaction; this promotes engagement of the pause-release factor p-TEFb and elongation of Ser2-phosphorylated RNA Pol II, driving transcription; reducing SMYD3 decreases myostatin and c-Met transcription and protects against glucocorticoid-induced myotube atrophy in vivo. Co-immunoprecipitation, ChIP, siRNA/shRNA knockdown, mouse model of dexamethasone-induced atrophy Genes & development High 23752591
2015 SMYD3 interacts with PC4 (human positive coactivator 4) and cooperates with it to drive expression of proliferation- and invasion-linked genes; PC4 depletion abolishes SMYD3-mediated H3K4me3 and target gene expression; SMYD3 and PC4 recruit each other to target genes in a mutually dependent manner. Co-immunoprecipitation, ChIP, siRNA knockdown, artificial tethering with catalytic mutant Nucleic acids research Medium 26350217
2016 SMYD3 methylates histone H2A.Z.1 at lysine 101 (H2A.Z.1K101me2), stabilizing H2A.Z.1 by preventing binding of the removal chaperone ANP32E and facilitating interaction with histone H3; SMYD3/H2A.Z.1K101me2 co-localizes at the cyclin A1 promoter, activates cyclin A1 expression, and promotes G1-S cell cycle progression and tumor formation. In vitro methyltransferase assay, Co-immunoprecipitation, ChIP, mutagenesis of K101, microarray, mouse tumor model Cancer research High 27569210
2016 Co-crystal structures of SMYD3 with VEGFR1 and MAP3K2 peptides revealed that MAP3K2 is a robust substrate due to a phenylalanine at the -2 position fitting a shallow hydrophobic pocket; VEGFR1 is a weaker substrate because the acceptor lysine is buried in the folded kinase domain, requiring drastic conformational rearrangement. X-ray co-crystallography, in vitro kinetic/biochemical assays, mutagenesis The Journal of biological chemistry High 26929412
2016 Co-crystal structure of SMYD3 with a MEKK2-peptide substrate and a SAM-competitive inhibitor (GSK2807, Ki = 14 nM) showed the inhibitor bridges the SAM-binding pocket and the substrate lysine tunnel; SMYD3 follows a partially processive methylation mechanism. X-ray crystallography (co-crystal with peptide substrate and inhibitor), kinetic characterization, biochemical inhibitor assays Structure High 27066749
2016 SMYD3 interacts with H3K4me3-modified histone tails, facilitating its recruitment to core promoter regions of active genes; Smyd3 binding correlates with increased RNA polymerase II density and is required for chemically induced liver and colon cancer formation in mice. ChIP-seq, Smyd3 knockout mouse model with chemical carcinogenesis, Co-immunoprecipitation with H3K4me3 Cancer cell High 26908355
2016 SMYD3 methylates AKT1 at lysine 14 in its PH domain; this methylation is required for AKT1 plasma membrane accumulation and for phosphorylation at threonine 308; K14-substituted AKT1 shows reduced membrane localization and lower growth-promoting activity. In vitro methyltransferase assay, Co-immunoprecipitation, site-directed mutagenesis, subcellular fractionation/imaging, SMYD3 KD and inhibitor treatment Oncotarget Medium 27626683
2017 SMYD3 trimethylates HER2 at lysine 175; this methylation promotes HER2 homodimerization; K175A substitution reduces homodimer formation and autophosphorylation; SMYD3 knockdown attenuates HER2 autophosphorylation in breast cancer cells. In vitro methyltransferase assay, Co-immunoprecipitation, site-directed mutagenesis, siRNA knockdown with phosphorylation readout Cancer medicine Medium 28639750
2019 SMYD3 directly interacts with SMAD3 and is required for SMAD3 association to chromatin at EMT gene regulatory regions in TGFβ-induced epithelial-mesenchymal transition; SMYD3 is dispensable for SMAD2/3 phosphorylation and nuclear translocation but is essential for SMAD3 chromatin binding. Co-immunoprecipitation, ChIP, SMYD3 knockdown and pharmacological inhibition (BCI121), zebrafish xenograft invasion model Nucleic acids research Medium 30544196
2015 The C-terminal TPR-like domain of SMYD3 mediates physical interaction with HSP90; this interaction is essential for basal SMYD3 histone methyltransferase activity; loss of SMYD3-HSP90 interaction causes SMYD3 mislocalization within the nucleus (loss of chromatin association), reducing cell proliferation. Co-immunoprecipitation, domain deletion/mutagenesis, in vitro methyltransferase assay, subcellular localization assay (immunofluorescence/fractionation), cell proliferation assay Oncotarget Medium 25738358
2010 SMYD3 interacts with HTLV-1 Tax protein via the C-terminal 180 amino acids of SMYD3; SMYD3 dominates the subcellular localization of Tax, tethering it to the cytoplasm, which enhances Tax-mediated NF-κB activation; SMYD3 knockdown attenuates this NF-κB activation. Co-immunoprecipitation, in vitro pull-down, colocalization (confocal microscopy), reporter gene assay, shRNA knockdown Cancer science Medium 21054678
2014 SMYD3 interacts with HCV NS5A protein via the MYND domain of SMYD3 and domain III of NS5A; SMYD3 overexpression decreases intracellular and extracellular HCV titers without affecting viral RNA replication, indicating SMYD3 negatively affects virus particle production in an NS5A-dependent manner. Co-immunoprecipitation, colocalization, mutational analysis (domain mapping), viral titer assay Virology Medium 25092459
2019 SMYD3 interacts directly with p53 via its post-SET domain; SMYD3 promotes p53 translocation from nucleus to cytoplasm and ubiquitination (independent of MDM2), forming a complex with UBE2R2 (an E2 ubiquitin-conjugating enzyme); SMYD3 ubiquitinates p53 at lysines 381, 382, and 386. Co-immunoprecipitation, mass spectrometry identification of UBE2R2, domain mapping (post-SET), ubiquitination assay, site-directed mutagenesis of p53 K381/382/386 Carcinogenesis Medium 31002112
2020 ATM phosphorylates SMYD3, enabling formation of a multiprotein complex of ATM, SMYD3, CHK2, and BRCA2 required for RAD51 loading at DNA double-strand break sites and completion of homologous recombination (HR); pharmacological SMYD3 inhibition sensitizes HR-proficient cancer cells to PARP inhibitors. Co-immunoprecipitation, use of ATM phosphorylation-deficient SMYD3 mutant variant, RAD51 focus formation assay, PARP inhibitor sensitivity assay iScience Medium 33205017
2022 SMYD3 methylates RNF113A, and this methylation impairs RNF113A interaction with the phosphatase PP4, controlling RNF113A phosphorylation levels; this cross-talk (methylation-phosphorylation) promotes RNF113A E3 ligase activity essential for the alkylation damage response, conferring SCLC resistance to alkylating chemotherapy; SMYD3 inhibition restores SCLC sensitivity. In vitro methyltransferase assay, Co-immunoprecipitation, phosphorylation assays, RNF113A ubiquitin ligase activity assay, SMYD3 inhibitor treatment in SCLC cells Cancer discovery High 35819319
2023 SMYD3 binds to and regulates transcription of UHRF1; UHRF1 (a reader of H3K9me3) recruits DNMT1 to silence immune-related gene promoters; SMYD3 additionally deposits H4K20me3 at intragenic regions of immune-related genes to maintain their repression; SMYD3 depletion upregulates type I interferon response genes and increases CD8+ T cell infiltration, sensitizing tumors to anti-PD-1 therapy. ChIP-seq, siRNA/shRNA knockdown, gene expression analysis, in vivo mouse tumor model with anti-PD-1 treatment, H4K20me3 ChIP Cell reports Medium 37463106
2023 SMYD3 methylates MAP3K2 in prostate cancer cells, promoting epithelial-mesenchymal transition-associated behaviors by altering vimentin abundance; SMYD3-MAP3K2 signaling creates a positive feedback loop that sustains high SMYD3 levels; catalytic mutant SMYD3 fails to promote these phenotypes. In vitro methyltransferase assay, catalytic mutant SMYD3, mouse xenograft models, vimentin western blot, EMT assays Science advances Medium 37976356
2022 SMYD3 binds to and stabilizes HIF1α (independent of its methyltransferase activity and independent of prolyl hydroxylase/VHL pathways), enhancing HIF1α transcriptional activity under hypoxia; SMYD3 promotes reactive oxygen species accumulation and hypoxia-induced apoptosis; smyd3-null zebrafish exhibit higher hypoxia tolerance. Co-immunoprecipitation, western blot stability assay, enzymatic-dead mutant, zebrafish knockout model, reporter assay The Journal of biological chemistry Medium 36273580
2020 SMYD3 binds to the promoter of PARP16 and increases H3K4me3 at this locus to activate PARP16 transcription; PARP16 in turn ADP-ribosylates PERK and IRE1α to promote unfolded protein response (UPR) and vascular smooth muscle cell proliferation; SMYD3-PARP16 axis mediates neointimal hyperplasia after vascular injury. ChIP-seq, ChIP-qPCR, Co-immunoprecipitation, SMYD3/PARP16 knockdown, ADP-ribosylation assay, mouse vascular injury model Acta pharmaceutica Sinica. B Medium 34094832
2023 In Alzheimer's disease/tauopathy context, elevated Smyd3 upregulates Fbxo2 (an E3 ubiquitin ligase) via H3K4me3 at the Fbxo2 promoter; Fbxo2 promotes NR1 (NMDAR subunit) ubiquitination and degradation; pharmacological Smyd3 inhibition (BCI-121) rescues NMDAR function and cognitive deficits in P301S Tau mice. ChIP, western blot of H3K4me3, Smyd3 inhibitor treatment, Fbxo2 knockdown rescue, electrophysiology, behavioral assays in mouse model Nature communications Medium 36609445
2018 SMYD3 interacts with ANKHD1 (identified by mass spectrometry of H3K4me3 pulldown); ANKHD1 binds H3K4me3 in SMYD3-overexpressing cells and is required for SMYD3-mediated SLUG gene activation (via H3K4me3, H3K9Ac, H3K14Ac); ANKHD1 knockdown attenuates SMYD3-dependent HCC migration and invasion. Mass spectrometry, Co-immunoprecipitation, ChIP, EMSA, luciferase reporter, siRNA knockdown Journal of experimental & clinical cancer research Medium 30646949
2020 SMYD3 nuclear-cytoplasmic distribution is regulated by cell geometry (shape and aspect ratio) in myoblasts via acto-myosin cytoskeleton; elongated cell geometries reduce SMYD3 nuclear import; cytoskeletal acto-myosin drugs induce SMYD3 nuclear accumulation; SMYD3 redistribution correlates with changes in trimethylation (Kme3) but not dimethylation levels. Live-cell imaging, pharmacological cytoskeletal perturbation, subcellular fractionation, immunofluorescence in micropatterned cells Scientific reports Medium 33244033
2019 SMYD3 is recruited by Ebola virus nucleoprotein (NP) to viral inclusion bodies; SMYD3 depletion suppresses EBOV mRNA production; SMYD3 promotes NP-VP30 interaction in a dose-dependent manner, thereby facilitating viral mRNA transcription. Co-immunoprecipitation, mass spectrometry (NP pulldown), minigenome replication system, siRNA knockdown with mRNA quantification Emerging microbes & infections Medium 31516086
2021 SMYD3 directly binds to the Cdkn1a (p21) promoter and increases H3K4me3 levels there, elevating p21 expression and driving senescence-associated phenotypes in endothelial cells; Smyd3 knockout mice are protected from Angiotensin II-induced vascular senescence. ChIP, Smyd3 knockout mouse model, siRNA knockdown, SMYD3 overexpression, Smyd3 inhibitor treatment Aging cell Medium 32779886

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nature cell biology 594 15235609
2014 SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 318 24847881
2006 Enhanced SMYD3 expression is essential for the growth of breast cancer cells. Cancer science 215 16441421
2010 Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. Genes, chromosomes & cancer 172 20725992
2011 SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. Cancer research 149 22194464
2012 Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics 148 22419068
2007 The lysine 831 of vascular endothelial growth factor receptor 1 is a novel target of methylation by SMYD3. Cancer research 143 18006819
2016 Smyd3 Is a Transcriptional Potentiator of Multiple Cancer-Promoting Genes and Required for Liver and Colon Cancer Development. Cancer cell 120 26908355
2015 A SMYD3 Small-Molecule Inhibitor Impairing Cancer Cell Growth. Journal of cellular physiology 98 25728514
2005 A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5' flanking region of SMYD3 is a risk factor for human cancers. Nature genetics 97 16155568
2007 The telomerase reverse transcriptase (hTERT) gene is a direct target of the histone methyltransferase SMYD3. Cancer research 93 17363582
2012 Epigenetic regulation of miR-124 by hepatitis C virus core protein promotes migration and invasion of intrahepatic cholangiocarcinoma cells by targeting SMYD3. FEBS letters 87 22819820
2018 The interaction of lncRNA EZR-AS1 with SMYD3 maintains overexpression of EZR in ESCC cells. Nucleic acids research 85 29253179
2009 Requirement of histone methyltransferase SMYD3 for estrogen receptor-mediated transcription. The Journal of biological chemistry 80 19509295
2019 SMYD3 promotes the epithelial-mesenchymal transition in breast cancer. Nucleic acids research 75 30544196
2013 The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy. Genes & development 70 23752591
2015 Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells. Nucleic acids research 69 26350217
2015 Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal immunology 65 25669152
2015 SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3. Oncotarget 65 25980436
2013 SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription. Journal of the National Cancer Institute 65 24174655
2011 Smyd3 is required for the development of cardiac and skeletal muscle in zebrafish. PloS one 61 21887258
2020 SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways. Cancers 59 31935919
2011 Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding. Nucleic acids research 58 21266482
2021 SMYD3: a regulator of epigenetic and signaling pathways in cancer. Clinical epigenetics 56 33637115
2019 Amplification of SMYD3 promotes tumorigenicity and intrahepatic metastasis of hepatocellular carcinoma via upregulation of CDK2 and MMP2. Oncogene 56 30842588
2016 Smyd3-associated regulatory pathways in cancer. Seminars in cancer biology 56 27554136
2009 Knockdown of SMYD3 by RNA interference down-regulates c-Met expression and inhibits cells migration and invasion induced by HGF. Cancer letters 53 19321255
2007 Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells. Oncogene 53 17998933
2018 SMYD3 controls a Wnt-responsive epigenetic switch for ASCL2 activation and cancer stem cell maintenance. Cancer letters 52 29746925
2013 Histone methyltransferase SMYD3 promotes MRTF-A-mediated transactivation of MYL9 and migration of MCF-7 breast cancer cells. Cancer letters 52 24189459
2018 Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation. PloS one 51 29856759
2016 Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets. Structure (London, England : 1993) 49 27066749
2016 SMYD3-Mediated H2A.Z.1 Methylation Promotes Cell Cycle and Cancer Proliferation. Cancer research 49 27569210
2015 Upregulated SMYD3 promotes bladder cancer progression by targeting BCLAF1 and activating autophagy. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 49 26676636
2008 Knockdown of SMYD3 by RNA interference inhibits cervical carcinoma cell growth and invasion in vitro. BMB reports 48 18452649
2015 C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis. Oncotarget 47 25738358
2016 SMYD3-mediated lysine methylation in the PH domain is critical for activation of AKT1. Oncotarget 45 27626683
2016 SMYD3 stimulates EZR and LOXL2 transcription to enhance proliferation, migration, and invasion in esophageal squamous cell carcinoma. Human pathology 42 26980013
2010 Effects of SMYD3 over-expression on cell cycle acceleration and cell proliferation in MDA-MB-231 human breast cancer cells. Medical oncology (Northwood, London, England) 42 20957523
2019 Overexpression of SMYD3 in Ovarian Cancer is Associated with Ovarian Cancer Proliferation and Apoptosis via Methylating H3K4 and H4K20. Journal of Cancer 40 31417652
2020 Histone methyltransferase Smyd3 is a new regulator for vascular senescence. Aging cell 39 32779886
2019 SMYD3 promotes implant metastasis of ovarian cancer via H3K4 trimethylation of integrin promoters. International journal of cancer 37 31503345
2017 A High-Throughput Dose-Response Cellular Thermal Shift Assay for Rapid Screening of Drug Target Engagement in Living Cells, Exemplified Using SMYD3 and IDO1. SLAS discovery : advancing life sciences R & D 37 28957646
2007 Silencing SMYD3 in hepatoma demethylates RIZI promoter induces apoptosis and inhibits cell proliferation and migration. World journal of gastroenterology 37 17963297
2019 ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 35 30646949
2021 LncRNA LTSCCAT promotes tongue squamous cell carcinoma metastasis via targeting the miR-103a-2-5p/SMYD3/TWIST1 axis. Cell death & disease 34 33542221
2016 Structural Basis for Substrate Preference of SMYD3, a SET Domain-containing Protein Lysine Methyltransferase. The Journal of biological chemistry 34 26929412
2019 Small-molecule inhibitors of lysine methyltransferases SMYD2 and SMYD3: current trends. Future medicinal chemistry 33 30998113
2008 Hepatitis B virus X protein upregulates expression of SMYD3 and C-MYC in HepG2 cells. Medical oncology (Northwood, London, England) 32 19082926
2017 Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization. Cancer medicine 31 28639750
2014 Lysine methylation in cancer: SMYD3-MAP3K2 teaches us new lessons in the Ras-ERK pathway. BioEssays : news and reviews in molecular, cellular and developmental biology 31 25382779
2014 Overexpression of SMYD3 was associated with increased STAT3 activation in gastric cancer. Medical oncology (Northwood, London, England) 29 25471787
2011 Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells. Acta biochimica et biophysica Sinica 29 21450690
2010 Novobiocin decreases SMYD3 expression and inhibits the migration of MDA-MB-231 human breast cancer cells. IUBMB life 29 20039369
2020 Chitooligosaccharides Modulate Glucose-Lipid Metabolism by Suppressing SMYD3 Pathways and Regulating Gut Microflora. Marine drugs 28 31968646
2017 ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells. Journal of gastric cancer 27 29302370
2020 VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR. Oncogene 26 32291411
2020 SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation. Acta pharmaceutica Sinica. B 26 34094832
2023 Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model. Nature communications 25 36609445
2023 SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck. Cell reports 25 37463106
2022 SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk. Cancer discovery 25 35819319
2016 Residual expression of SMYD2 and SMYD3 is associated with the acquisition of complex karyotype in chronic lymphocytic leukemia. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 26790435
2009 Effects of SMYD3 overexpression on transformation, serum dependence, and apoptosis sensitivity in NIH3T3 cells. IUBMB life 25 19472189
2019 Overexpression of the SMYD3 Promotes Proliferation, Migration, and Invasion of Pancreatic Cancer. Digestive diseases and sciences 24 31441002
2017 MiR-346 suppresses cell proliferation through SMYD3 dependent approach in hepatocellular carcinoma. Oncotarget 24 29029425
2014 Effect of the downregulation of SMYD3 expression by RNAi on RIZ1 expression and proliferation of esophageal squamous cell carcinoma. Oncology reports 24 24993551
2019 Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3. ACS medicinal chemistry letters 23 31223458
2021 SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters. Cell death & disease 22 34301921
2019 Host factor SMYD3 is recruited by Ebola virus nucleoprotein to facilitate viral mRNA transcription. Emerging microbes & infections 22 31516086
2010 SMYD3 interacts with HTLV-1 Tax and regulates subcellular localization of Tax. Cancer science 22 21054678
2021 Discovery of the SMYD3 Inhibitor BAY-6035 Using Thermal Shift Assay (TSA)-Based High-Throughput Screening. SLAS discovery : advancing life sciences R & D 21 34154424
2019 SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination. Carcinogenesis 21 31002112
2019 The SMYD3 methyltransferase promotes myogenesis by activating the myogenin regulatory network. Scientific reports 21 31754141
2015 Histone methyltransferase Smyd3 regulates early embryonic lineage commitment in mice. Reproduction (Cambridge, England) 21 25918436
2008 Association of the variable number of tandem repeats polymorphism in the promoter region of the SMYD3 gene with risk of esophageal squamous cell carcinoma in relation to tobacco smoking. Cancer science 21 18294291
2020 Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality. iScience 20 33205017
2023 Histone lysine methyltransferase SMYD3 promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 transcription. Clinical epigenetics 19 37237385
2014 The lysine methyltransferase SMYD3 interacts with hepatitis C virus NS5A and is a negative regulator of viral particle production. Virology 18 25092459
2023 SMYD3 drives the proliferation in gastric cancer cells via reducing EMP1 expression in an H4K20me3-dependent manner. Cell death & disease 17 37386026
2022 The SMYD3-MTHFD1L-formate metabolic regulatory axis mediates mitophagy to inhibit M1 polarization in macrophages. International immunopharmacology 17 36330911
2021 A SMYD3/ITGB6/TGFβ1 Positive Feedback Loop Promotes the Invasion and Adhesion of Ovarian Cancer Spheroids. Frontiers in oncology 17 34621667
2020 Smyd3-PARP16 axis accelerates unfolded protein response and vascular aging. Aging 17 33144524
2020 Cell geometry and the cytoskeleton impact the nucleo-cytoplasmic localisation of the SMYD3 methyltransferase. Scientific reports 17 33244033
2022 Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3. European journal of medicinal chemistry 16 36116234
2015 Histone methyltransferase SMYD3 regulates the expression of transcriptional factors during bovine oocyte maturation and early embryonic development. Cytotechnology 16 25563599
2018 SMYD3 promoter hypomethylation is associated with the risk of colorectal cancer. Future oncology (London, England) 15 29969917
2018 SMYD3-associated pathway is involved in the anti-tumor effects of sulforaphane on gastric carcinoma cells. Food science and biotechnology 15 30263847
2023 Mechanical pressure-induced dedifferentiation of myofibroblasts inhibits scarring via SMYD3/ITGBL1 signaling. Developmental cell 14 37192621
2023 SMYD3 induces sorafenib resistance by activating SMAD2/3-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. iScience 14 37534166
2023 SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages. International immunopharmacology 14 38091832
2021 Elevated placental histone H3K4 methylation via upregulated histone methyltransferases SETD1A and SMYD3 in preeclampsia and its possible involvement in hypoxia-induced pathophysiological process. Placenta 14 34560329
2024 Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC. Journal of advanced research 13 39159723
2023 The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer. Science advances 13 37976356
2022 Identifying novel SMYD3 interactors on the trail of cancer hallmarks. Computational and structural biotechnology journal 13 35495117
2021 H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation. Arteriosclerosis, thrombosis, and vascular biology 13 33827259
2021 Novel insights into SMYD2 and SMYD3 inhibitors: from potential anti-tumoural therapy to a variety of new applications. Molecular biology reports 13 34510321
2019 STAT3-induced SMYD3 transcription enhances chronic lymphocytic leukemia cell growth in vitro and in vivo. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 13 31218443
2022 Methyltransferase SMYD3 impairs hypoxia tolerance by augmenting hypoxia signaling independent of its enzymatic activity. The Journal of biological chemistry 12 36273580
2021 Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase. Chembiochem : a European journal of chemical biology 12 33400854
2016 Therapeutical potential of deregulated lysine methyltransferase SMYD3 as a safe target for novel anticancer agents. Expert opinion on therapeutic targets 12 28019723