ArticleNature2014
SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 226 papers, 2 of them syntheses that pooled it.
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Who cites it
226 citing papers in PubMed, 2 syntheses or guidelines pooled it, 406 citations in OpenAlex.
- Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review.Signal transduction and targeted therapy · 2023Pooled it
- Pooled it
- SETD8-mediated mono-methylation of YAP at K76 promotes K48-linked polyubiquitination and degradation to suppress colorectal cancer.Cell death and differentiation · 2026Article
- Vernodalin andBiomedicines · 2026Article
- NSD1-Mediated PPARγ Methylation Enhances PTEN Activity to Suppress Glycolysis and Tumor Progression in Endometrial Cancer.Cancer research · 2026Article
- A novel molecule ZYZ329 targeting histone methyltransferase SMYD3 suppresses pathological angiogenesis via the driven mitochondrial ROS/HIF-1α/VEGFA axis.Journal of translational medicine · 2026Article
- KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage.bioRxiv : the preprint server for biology · 2026Article
- Non-Histone Lysine Modifications in Tumor Microenvironment: Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- Loss of histone methyltransferase Smyd3 triggers WAT browning and adaptive thermogenesis via enhancing PPARγ expression in a H4K20me3-dependent manner.Journal of translational medicine · 2025Article
- The Identification by Shotgun Proteomics with High-Resolution Tandem Mass-Spectrometry of Histone Isoforms' Hypermethylation Phenotype as a Hallmark Characteristic of Human-IDH-Mutant High-Grade Gliomas: Epigenetic Applications for Genotoxicity-Based Biomarkers and Cancer Therapy Targets.Journal of proteome research · 2025Article
- Bifaceted functions of histone methyltransferases.Epigenomics · 2025Article
- Microbiota-driven epigenetic modifications in gastrointestinal cancer: Implications for pathogenesis and therapeutic strategies.World journal of microbiology & biotechnology · 2025Review
- Matrix stiffness-dependent PD-L2 deficiency improves SMYD3/xCT-mediated ferroptosis and the efficacy of anti-PD-1 in HCC.Journal of advanced research · 2025Article
- Tailoring a novel colorectal cancer stem cell-targeted therapy by inhibiting the SMYD3/c-MYC axis.Signal transduction and targeted therapy · 2025Article
- Oncogenic activation of SMYD3-SHCBP1 promotes breast cancer development and is coupled with resistance to immune therapy.Cell death & disease · 2025Article
- Combinatorial In Vivo Genome Editing Identifies Widespread Epistasis and an Accessible Fitness Landscape During Lung Tumorigenesis.Molecular biology and evolution · 2025Article
- Facile preparation of sulfonium peptide and protein probes for selective crosslinking of methyllysine readers.Chemical science · 2025Article
- Direct lysine dimethylation of IRF3 by the methyltransferase SMYD3 attenuates antiviral innate immunity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- SMYD3 drives cell cycle and epithelial-mesenchymal transition pathways through dual gene transcriptional repression and activation in HPV-negative head and neck cancer.Scientific reports · 2025Article
- Development of a High-Throughput Platform for Quantitation of Histone Modifications on a New QTOF Instrument.Molecular & cellular proteomics : MCP · 2025Article
166 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.