Affinage

SMYD3

Histone-lysine N-methyltransferase SMYD3 · UniProt Q9H7B4

Length
428 aa
Mass
49.1 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMYD3 is a SET-domain lysine methyltransferase that controls oncogenic and stress-response gene programs by acting on both chromatin and cytoplasmic signaling substrates (PMID:15235609, PMID:24847881). In the nucleus, its SET domain methylates histone H3K4 (including di- and trimethylation), H4K5, and histone variant H2A.Z.1 at K101, the latter stabilizing the nucleosome against the ANP32E removal chaperone to activate cyclin A1 and drive G1-S progression (PMID:15235609, PMID:22419068, PMID:27569210). SMYD3 is recruited to specific promoters through interaction with RNA polymerase II, the coactivator PC4, BRD4 (which engages p-TEFb to release paused Pol II), the estrogen receptor, SMAD3 during TGFβ-driven EMT, and ANKHD1, thereby transactivating oncogenes, cell-cycle genes, and EMT regulators including Myc, Ctnnb1, hTERT, and SLUG (PMID:19509295, PMID:26908355, PMID:23752591, PMID:26350217, PMID:30544196, PMID:17363582, PMID:30646949). Beyond gene activation it also enforces gene silencing, activating UHRF1 transcription and depositing intragenic H4K20me3 to repress type I interferon and antigen-presentation genes, restraining antitumor immunity (PMID:37463106). In the cytoplasm SMYD3 methylates non-histone substrates to amplify kinase signaling: MAP3K2-K260 methylation blocks PP2A binding to potentiate Ras/Raf/MEK/ERK signaling and Ras-driven tumorigenesis, AKT1-K14 promotes T308 phosphorylation and membrane localization, and HER2-K175 trimethylation promotes homodimerization and autophosphorylation (PMID:24847881, PMID:27626683, PMID:28639750). SMYD3 additionally couples to the DNA damage and chemoresistance machinery, methylating RNF113A to sustain its E3 ligase activity in the alkylation response and forming an ATM–CHK2–BRCA2 complex required for RAD51 loading in homologous recombination (PMID:35819319, PMID:33205017). Structurally, a C-terminal TPR domain together with the SET and post-SET domains forms a deep substrate-binding pocket; HSP90 binding to this TPR domain and N-terminal cleavage stimulate catalytic activity, while DNA binding further enhances HMTase activity (PMID:21266482, PMID:17998933, PMID:25738358). Genetic ablation establishes a causal in vivo requirement for SMYD3 across chemically induced liver/colon cancer, vascular senescence and neointimal hyperplasia, muscle atrophy, and Tau-driven cognitive decline (PMID:26908355, PMID:23752591, PMID:32779886, PMID:34094832, PMID:36609445).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2004 High

    Established SMYD3 as a sequence-specific transcriptional activator with intrinsic H3K4 methyltransferase activity, defining its founding role in oncogene expression.

    Evidence In vitro HMTase assay, Co-IP with Pol II via HELZ, promoter motif binding, siRNA proliferation readout

    PMID:15235609

    Open questions at the time
    • Did not resolve full substrate spectrum beyond H3K4
    • Mechanism of HSP90 stimulation not yet structurally defined
  2. 2007 Medium

    Showed SMYD3 acts beyond chromatin by methylating a receptor tyrosine kinase, and mapped intrinsic negative regulation by its N-terminus.

    Evidence In vitro methylation with MS site mapping (VEGFR1-K831), N-terminal truncation/mutagenesis with HMTase assay and HSP90 Co-IP

    PMID:17998933 PMID:18006819

    Open questions at the time
    • VEGFR1 was later shown to be a weak substrate structurally
    • Physiological trigger for N-terminal cleavage unknown
  3. 2011 High

    Provided the first full-length structure, revealing the TPR-SET-postSET substrate pocket and that DNA binding stimulates catalysis.

    Evidence X-ray crystallography with SAH, Tyr239 active-site mutagenesis, DNA-binding HMTase assay

    PMID:21266482

    Open questions at the time
    • Did not capture peptide substrates in the pocket
    • MYND-mediated DNA binding mechanism inferred not proven
  4. 2014 High

    Defined the central oncogenic non-histone mechanism: MAP3K2-K260 methylation displaces PP2A to potentiate Ras/ERK signaling and drive tumorigenesis in vivo.

    Evidence Protein-array substrate ID, in vitro methylation, Co-IP of PP2A displacement, Kras-driven mouse cancer models, MEK-inhibitor synergy

    PMID:24847881

    Open questions at the time
    • Did not quantify relative flux through histone versus MAP3K2 axes
    • Reader/effector of K260me beyond PP2A not detailed
  5. 2016 High

    Co-crystal structures explained substrate selectivity (-2 phenylalanine of MAP3K2) over VEGFR1 and validated a tractable active-site inhibitor.

    Evidence Co-crystal structures with VEGFR1/MAP3K2 peptides, kinetic analysis, GSK2807 inhibitor characterization

    PMID:26929412 PMID:27066749

    Open questions at the time
    • Structural basis for histone versus non-histone preference not resolved
    • Processivity implications for cellular output untested
  6. 2016 Medium

    Expanded the nuclear and cytoplasmic substrate repertoire to a histone variant and a survival kinase, linking SMYD3 directly to cell-cycle progression and AKT activation.

    Evidence In vitro methylation + MS (H2A.Z.1-K101, AKT1-K14), Co-IP with ANP32E/H3, mutagenesis, membrane fractionation, ChIP, mouse tumor model

    PMID:27569210 PMID:27626683

    Open questions at the time
    • Single-lab substrate identifications without independent replication
    • Stoichiometry of these marks in vivo unclear
  7. 2017 Medium

    Extended kinase-activating methylation to HER2, coupling SMYD3 to receptor dimerization in breast cancer.

    Evidence In vitro methylation, K175A mutagenesis, Co-IP homodimerization, siRNA, phospho-immunoblot

    PMID:28639750

    Open questions at the time
    • Direct K175me detection in patient tumors not shown
    • Mechanism linking methylation to dimer interface undefined
  8. 2020 Medium

    Connected SMYD3 to the homologous recombination machinery and to mechanical control of its compartmental localization.

    Evidence Co-IP of ATM-SMYD3-CHK2-BRCA2 complex, RAD51 foci, PARPi synthetic lethality; live imaging with acto-myosin perturbation and compartment-specific Kme3

    PMID:33205017 PMID:33244033

    Open questions at the time
    • Whether SMYD3 methylation activity (vs scaffolding) drives HR is unresolved
    • Cytoplasmic Kme3 substrates not individually mapped in the geometry study
  9. 2022 High

    Showed SMYD3 methylation-phosphorylation cross-talk on RNF113A governs alkylation-damage response and chemosensitivity.

    Evidence In vitro methylation, RNF113A-PP4 Co-IP, pharmacological SMYD3 inhibition, chemosensitivity and in vivo SCLC model

    PMID:35819319

    Open questions at the time
    • Methylated residue(s) on RNF113A not specified here
    • Generality across alkylating agents not fully mapped
  10. 2023 High

    Revealed dual transcriptional logic — silencing immune genes via UHRF1/H4K20me3 and tuning substrate stability via EZH2 methylation — and a neurological role through Fbxo2-NMDAR control.

    Evidence ChIP-seq/RNA-seq with UHRF1 epistasis and anti-PD-1 model; EZH2-K421 methylation/ubiquitination/metastasis assays; Tau-mouse ChIP, ubiquitination, electrophysiology and behavior

    PMID:36127410 PMID:36609445 PMID:37463106

    Open questions at the time
    • How SMYD3 switches between activating and repressive chromatin states is unresolved
    • EZH2-K421 degradation places SMYD3 as metastasis-restraining, contrasting its oncogenic roles — context determinants unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what determines the partitioning of SMYD3 between its histone-modifying, transcriptional-scaffolding, and cytoplasmic kinase-methylating functions in a given cell, and which of its many substrates dominate in each disease context.
  • No unified model integrating localization control with substrate choice
  • Relative contribution of catalytic vs scaffolding activity per pathway untested
  • Substrate hierarchy in vivo unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2
Localization
GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1 R-HSA-168256 Immune System 1
Partners
ANKHD1BRD4EZH2HSP90MAP3K2PC4RNF113ASMAD3
Complex memberships
ATM-SMYD3-CHK2-BRCA2 complexRNA Pol II complex (via HELZ)SMYD3-UBE2R2-p53 complex

Evidence

Reading pass · 33 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 in the presence of heat-shock protein HSP90A. SMYD3 forms a complex with RNA polymerase II through an interaction with the RNA helicase HELZ and binds to the promoter motif 5'-CCCTCC-3' to transactivate downstream oncogenes and cell-cycle genes. In vitro methyltransferase assay, Co-immunoprecipitation, promoter binding assay, siRNA knockdown with proliferation readout Nature cell biology High 15235609
2007 SMYD3 methylates vascular endothelial growth factor receptor 1 (VEGFR1) at lysine 831, located in the kinase domain; 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
2007 N-terminal cleavage of SMYD3 (removing 34 amino acids) increases its histone methyltransferase activity. The N-terminal region mediates association with HSP90alpha, and mutations at conserved glycines 15 and 17 also increase HMTase activity, indicating the N-terminus negatively regulates enzymatic activity. Protein truncation/mutagenesis, in vitro HMTase assay, Co-immunoprecipitation Oncogene Medium 17998933
2011 Crystal structure of full-length human SMYD3 in complex with S-adenosyl-L-homocysteine at 2.8 Å resolution reveals that the C-terminal domain contains a tetratricopeptide repeat (TPR) domain that together with the SET and post-SET domains forms a deep, narrow substrate-binding pocket. The hydroxyl group of Tyr239 is critical for enzymatic activity. DNA binding stimulates SMYD3 HMTase activity, potentially mediated via the MYND domain. X-ray crystallography, mutagenesis (Tyr239), biochemical HMTase assay, DNA-binding assay Nucleic acids research High 21266482
2012 SMYD3 catalyzes methylation of histone H4 at lysine 5 (H4K5me); this mark is detected in diverse cell types and is attenuated upon SMYD3 depletion. SMYD3-driven cancer cell phenotypes require its enzymatic activity. Mass spectrometry, immunoblot with H4K5me-specific antibody, siRNA knockdown, cancer cell phenotype assays Epigenetics Medium 22419068
2014 SMYD3 methylates MAP3K2 (MEKK2) at lysine 260, potentiating Ras/Raf/MEK/ERK signaling. The PP2A phosphatase complex binds MAP3K2 and this interaction is blocked by SMYD3-mediated methylation, releasing MAP3K2 from negative regulation. Abrogating SMYD3 catalytic activity inhibits Ras-driven pancreatic and lung adenocarcinoma development in mouse models. Protein array substrate identification, in vitro methyltransferase assay, Co-IP, mouse cancer models (Kras-driven), MEK inhibitor synergy assay, site-directed mutagenesis (K260) Nature High 24847881
2015 The C-terminal TPR-like domain of SMYD3 mediates physical interaction with HSP90; this interaction is required for basal HMTase activity and for HSP90-enhanced enzyme activity. Loss of SMYD3-HSP90 interaction causes SMYD3 mislocalization within the nucleus and loss of chromatin association, reducing SMYD3-mediated cell proliferation. Co-immunoprecipitation, domain-deletion mutagenesis, chromatin fractionation, HMTase assay, cell proliferation assay Oncotarget Medium 25738358
2015 SMYD3 functions as a coactivator of estrogen receptor alpha (ERα); it directly interacts with the ligand-binding domain of ERα and is recruited to ER target gene promoters upon estrogen stimulation, where it catalyzes H3K4 di- and trimethylation. SMYD3 knockdown abolishes ER-regulated transcription. Co-immunoprecipitation, ChIP assay, siRNA knockdown, luciferase reporter assay The Journal of biological chemistry Medium 19509295
2016 Crystal structures of SMYD3 co-crystallized with VEGFR1 and MAP3K2 peptides reveal that a phenylalanine at the -2 position of MAP3K2 fits into a shallow hydrophobic pocket on SMYD3, explaining MAP3K2's preference as a substrate over VEGFR1. SMYD3 follows a partially processive mechanism. The inhibitor GSK2807 (Ki=14 nM) bridges the SAM-binding and substrate lysine tunnel pockets. X-ray co-crystal structures, kinetic characterization, inhibitor design and structural validation Structure (London, England : 1993) High 27066749
2016 Co-crystal structures of SMYD3 with VEGFR1 and MAP3K2 peptides provide structural basis for substrate preference: the phenylalanine at -2 of MAP3K2 confers robust catalytic activity whereas VEGFR1 lysine location in a folded kinase domain requires unfavorable conformational rearrangement, explaining weak activity toward VEGFR1. X-ray crystallography, in vitro biochemical methylation assays with peptide substrates The Journal of biological chemistry High 26929412
2016 SMYD3 methylates histone H2A.Z.1 at lysine 101 (H2A.Z.1K101me2), increasing its stability by preventing binding to the removal chaperone ANP32E and facilitating interaction with histone H3. This methylation event activates cyclin A1 expression at its promoter and drives G1-S progression. In vitro methyltransferase assay, mass spectrometry, Co-IP, microarray, ChIP assay, mutagenesis, mouse tumor model Cancer research Medium 27569210
2016 SMYD3 methylates AKT1 at lysine 14 in the PH domain both in vitro and in vivo; this methylation is required for AKT1 phosphorylation at threonine 308 (activation) and for plasma membrane accumulation of AKT1. SMYD3 knockdown or pharmacological inhibition attenuates T308 phosphorylation. In vitro methyltransferase assay, site-directed mutagenesis (K14 substitution), subcellular fractionation/membrane localization assay, siRNA knockdown, SMYD3 inhibitor treatment, cell growth assay Oncotarget Medium 27626683
2016 In mouse liver and colon cancer models, SMYD3 is localized in the nucleus, interacts with H3K4me3-modified histone tails, and is recruited to core promoter regions. SMYD3 binding increases RNA polymerase II density and transcriptional output of a specific set of oncogenes and cell proliferation genes, including Myc and Ctnnb1. Smyd3 knockout mice are resistant to chemically induced liver and colon cancer. ChIP-seq, RNA-seq, conditional Smyd3 knockout mouse model with chemical carcinogenesis, Co-IP with H3K4me3 tails Cancer cell High 26908355
2013 SMYD3 methyltransferase targets myostatin and c-Met gene regulatory regions in skeletal muscle cells and recruits the bromodomain protein BRD4 through protein-protein interaction. BRD4 recruitment by SMYD3 facilitates engagement of the pause-release factor p-TEFb and elongation of Ser2-phosphorylated RNA Pol II, activating myostatin and c-Met transcription. SMYD3 depletion prevents dexamethasone-induced muscle atrophy in mice. ChIP assay, Co-IP (SMYD3-BRD4 interaction), siRNA knockdown, JQ1 BRD4 inhibitor, in vivo mouse dexamethasone atrophy model Genes & development High 23752591
2015 SMYD3 interacts with positive coactivator PC4; this interaction is mutually required for SMYD3 and PC4 co-recruitment to target gene promoters and for SMYD3-mediated H3K4me3 and target gene expression. PC4 depletion abolishes SMYD3-driven H3K4me3 and oncogenic transcription. Co-immunoprecipitation, ChIP assay, siRNA knockdown of PC4, artificial tethering of SMYD3 mutant Nucleic acids research Medium 26350217
2019 SMYD3 directly interacts with SMAD3 (via Co-IP) and is indispensable for SMAD3 association to chromatin at EMT gene regulatory regions during TGFβ signaling. SMYD3 is not required for SMAD2/3 phosphorylation or nuclear translocation but is required for the final chromatin recruitment step. Pharmacological SMYD3 blockade reduces TGFβ-induced mesenchymal gene transcription and invasion in vivo (zebrafish xenograft). Co-immunoprecipitation, ChIP assay, siRNA/pharmacological inhibitor (BCI121), zebrafish xenograft invasion assay Nucleic acids research Medium 30544196
2017 SMYD3 trimethylates HER2 at lysine 175; this methylation enhances HER2 homodimerization, and the K175A substitution reduces homodimer formation and autophosphorylation. SMYD3 knockdown attenuates HER2 autophosphorylation in breast cancer cells. In vitro methyltransferase assay, site-directed mutagenesis (K175A), Co-IP homodimerization assay, siRNA knockdown, phosphorylation immunoblot Cancer medicine Medium 28639750
2022 SMYD3 methylates RNF113A, and this methylation impairs RNF113A's interaction with the phosphatase PP4, thereby controlling RNF113A phosphorylation levels; the methylation-phosphorylation cross-talk maintains RNF113A E3 ligase activity required for alkylation damage response. SMYD3 inhibition restores SCLC vulnerability to alkylating chemotherapy. In vitro methyltransferase assay, Co-IP (RNF113A-PP4 interaction assay), pharmacological SMYD3 inhibition, chemosensitivity assay, in vivo SCLC model Cancer discovery High 35819319
2020 SMYD3 phosphorylation by ATM kinase enables formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for RAD51 loading at DNA double-strand break sites and completion of homologous recombination. SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors. Co-IP of ATM-SMYD3-CHK2-BRCA2 complex, RAD51 foci assay, SMYD3 inhibitor + PARP inhibitor synthetic lethality assay, domain mapping using SMYD3 mutant variant iScience Medium 33205017
2010 SMYD3 directly interacts with HTLV-1 Tax protein via the C-terminal 180 amino acids of SMYD3; SMYD3 dominates the subcellular localization of Tax, promoting cytoplasmic retention of Tax and enhancing Tax-mediated NF-κB activation. SMYD3 knockdown attenuates NF-κB activation by cytoplasmic Tax. Co-immunoprecipitation, in vitro pull-down, co-localization microscopy, domain-deletion mutagenesis, NF-κB reporter assay, shRNA knockdown Cancer science Medium 21054678
2014 SMYD3 interacts with HCV NS5A via SMYD3's MYND domain and NS5A domain III (mapped by mutagenesis). SMYD3 overexpression decreases intracellular and extracellular HCV virus titers without affecting viral RNA replication, indicating SMYD3 negatively affects particle production in an NS5A-dependent manner. Co-immunoprecipitation, co-localization, mutagenesis of MYND domain and NS5A domain III, virus titer assay, RNA replication assay Virology Medium 25092459
2019 SMYD3 is recruited by Ebola virus nucleoprotein (NP) to viral inclusion bodies; SMYD3 depletion suppresses EBOV mRNA production and SMYD3 promotes NP-VP30 interaction in a dose-dependent manner, supporting viral transcription. Co-immunoprecipitation (SMYD3-NP), mass spectrometry, minigenome system, siRNA knockdown, co-localization, NP-VP30 interaction assay Emerging microbes & infections Medium 31516086
2007 SMYD3 occupies its binding motifs on the hTERT promoter and is required for H3K4 trimethylation at that locus. SMYD3 knockdown abolishes H3K4me3 at the hTERT promoter, attenuates c-MYC and Sp1 occupancy, reduces histone H3 acetylation, and decreases hTERT mRNA and telomerase activity. ChIP assay, siRNA knockdown, quantitative RT-PCR, telomerase activity assay Cancer research Medium 17363582
2020 SMYD3 directly binds the promoter region of Cdkn1a (p21), increases H3K4me3 at that locus, and elevates p21 expression, driving endothelial cell senescence-associated phenotypes. Smyd3 knockout mice are protected from Ang II-induced vascular senescence. ChIP assay, Smyd3 knockout mice, Ang II vascular senescence model, immunoblot, siRNA knockdown Aging cell Medium 32779886
2020 SMYD3 binds the promoter of PARP16 and increases H3K4me3 at that locus to activate PARP16 transcription. SMYD3-driven PARP16 upregulation activates ER stress/UPR and promotes smooth muscle cell proliferation and neointimal hyperplasia. Knockdown of either SMYD3 or PARP16 impedes ER stress and SMC proliferation. ChIP-seq, ChIP assay, siRNA knockdown, overexpression, in vivo neointimal hyperplasia model Acta pharmaceutica Sinica. B Medium 34094832
2023 SMYD3 methyltransferase is elevated in Alzheimer's disease PFC and P301S Tau mouse PFC; SMYD3-mediated H3K4me3 upregulates Fbxo2 (E3 ubiquitin ligase), which increases ubiquitination and degradation of NMDAR subunit NR1. SMYD3 inhibition rescues synaptic NMDAR function and cognitive deficits in P301S Tau mice. SMYD3 inhibitor (BCI-121) treatment, electrophysiology, behavioral assays, ChIP assay, Fbxo2 knockdown, ubiquitination assay in mouse PFC Nature communications High 36609445
2023 SMYD3 methylates EZH2 at K421; this methylation accelerates EZH2 ubiquitin-proteasome degradation. Cells harboring non-methylated EZH2 (K421 mutant) show enhanced gastric cancer metastasis, indicating SMYD3-EZH2 methylation restricts rather than promotes metastasis via EZH2 stability. In vitro methyltransferase assay, site-directed mutagenesis (K421), ubiquitination assay, soft agar colony formation, in vivo metastasis model Cancer gene therapy Medium 36127410
2023 SMYD3 depletion in HPV-negative HNSCC induces upregulation of type I interferon response and antigen presentation genes. Mechanistically, SMYD3 binds and activates UHRF1 transcription; UHRF1 reads H3K9me3 at immune gene promoters, recruits DNMT1, and silences their expression. SMYD3 also deposits H4K20me3 intragentically to maintain repression of immune-related genes. In vivo, Smyd3 depletion increases CD8+ T cell infiltration and sensitivity to anti-PD-1 therapy. ChIP-seq, RNA-seq, siRNA/shRNA knockdown, in vivo syngeneic mouse model with anti-PD-1 treatment, UHRF1 epistasis experiments Cell reports High 37463106
2023 SMYD3-dependent MAP3K2 methylation promotes EMT-associated behaviors and vimentin upregulation in prostate cancer cells. A positive feedback loop exists whereby SMYD3-MAP3K2-MAPK signaling continually promotes high SMYD3 levels. Both in vitro and xenograft models show SMYD3 catalytic activity is required for these tumor-associated phenotypes. In vitro methyltransferase assay, mutagenesis, siRNA knockdown, mouse xenograft model, EMT marker immunoblot Science advances Medium 37976356
2020 SMYD3 nucleo-cytoplasmic localization is regulated by cell geometry (shape and aspect ratio) via cytoskeletal acto-myosin signaling; elongated shapes reduce nuclear SMYD3 import. Nuclear vs. cytoplasmic distribution of SMYD3 correlates with compartment-specific lysine trimethylation (Kme3) levels, consistent with SMYD3 having both nuclear and cytoplasmic substrates. Live imaging, pharmacological acto-myosin disruption, immunofluorescence with compartment-specific methylation readout Scientific reports Medium 33244033
2019 SMYD3 directly interacts with ANKHD1 (identified by mass spectrometry of H3K4me3 pulldown from SMYD3-overexpressing cells). ANKHD1 is required for SMYD3-mediated activation of SLUG gene transcription through H3K4me3 enrichment at the SLUG promoter; ANKHD1 knockdown attenuates the pro-migratory and pro-invasive effects of SMYD3. Mass spectrometry, Co-IP, ChIP (H3K4me3 at SLUG promoter), EMSA, siRNA epistasis (ANKHD1), migration/invasion assay Journal of experimental & clinical cancer research : CR Medium 30646949
2019 SMYD3 interacts with p53 directly via the post-SET domain; this interaction promotes p53 ubiquitination and proteasomal degradation independent of MDM2. SMYD3 interacts with the ubiquitin-conjugating enzyme UBE2R2, forming a SMYD3-UBE2R2-p53 complex that ubiquitinates p53 at lysines 381, 382, and 386. SMYD3 promotes p53 translocation from nucleus to cytoplasm. Co-immunoprecipitation, mass spectrometry, ubiquitination assay, domain-deletion (post-SET) mapping, site-directed mutagenesis of p53 lysines, subcellular fractionation Carcinogenesis Medium 31002112
2011 Smyd3 knockdown in zebrafish embryos using morpholino antisense oligonucleotides causes pericardial edema, trunk structure defects, and abnormal expression of heart-chamber markers (cmlc2, amhc, vmhc) and myogenic regulatory factors (myod, myog), establishing a role for Smyd3 in cardiac and skeletal muscle development. Morpholino knockdown in zebrafish, whole-mount in situ hybridization for developmental markers PloS one Medium 21887258

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 595 15235609
2014 SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 319 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 121 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 81 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 55 19321255
2013 Histone methyltransferase SMYD3 promotes MRTF-A-mediated transactivation of MYL9 and migration of MCF-7 breast cancer cells. Cancer letters 53 24189459
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
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 43 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
2020 Histone methyltransferase Smyd3 is a new regulator for vascular senescence. Aging cell 41 32779886
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
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
2021 LncRNA LTSCCAT promotes tongue squamous cell carcinoma metastasis via targeting the miR-103a-2-5p/SMYD3/TWIST1 axis. Cell death & disease 35 33542221
2019 ANKHD1 is required for SMYD3 to promote tumor metastasis in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 34 30646949
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) 33 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
2020 Chitooligosaccharides Modulate Glucose-Lipid Metabolism by Suppressing SMYD3 Pathways and Regulating Gut Microflora. Marine drugs 29 31968646
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
2017 ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells. Journal of gastric cancer 27 29302370
2023 Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model. Nature communications 26 36609445
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 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
2021 SMYD3 promotes hepatocellular carcinoma progression by methylating S1PR1 promoters. Cell death & disease 23 34301921
2019 Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3. ACS medicinal chemistry letters 23 31223458
2019 SMYD3 promotes epithelial ovarian cancer metastasis by downregulating p53 protein stability and promoting p53 ubiquitination. Carcinogenesis 22 31002112
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
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 22 18294291
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 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
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
2022 The SMYD3-MTHFD1L-formate metabolic regulatory axis mediates mitophagy to inhibit M1 polarization in macrophages. International immunopharmacology 18 36330911
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
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
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 15 39159723
2023 SMYD3 induces sorafenib resistance by activating SMAD2/3-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. iScience 15 37534166
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 15 34560329
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 The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer. Science advances 14 37976356
2023 SMYD3 activates the TCA cycle to promote M1-M2 conversion in macrophages. International immunopharmacology 14 38091832
2021 H3K4 Methyltransferase Smyd3 Mediates Vascular Smooth Muscle Cell Proliferation, Migration, and Neointima Formation. Arteriosclerosis, thrombosis, and vascular biology 14 33827259
2022 Identifying novel SMYD3 interactors on the trail of cancer hallmarks. Computational and structural biotechnology journal 13 35495117
2022 SMYD3 promotes aerobic glycolysis in diffuse large B-cell lymphoma via H3K4me3-mediated PKM2 transcription. Cell death & disease 13 36057625
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 SMYD3 regulates gastric cancer progression and macrophage polarization through EZH2 methylation. Cancer gene therapy 12 36127410
2016 Therapeutical potential of deregulated lysine methyltransferase SMYD3 as a safe target for novel anticancer agents. Expert opinion on therapeutic targets 12 28019723

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