SMYD3 Gene

HGNC Family	Zinc fingers, Chromatin-modifying enzymes
Name	SET and MYND domain containing 3
Description	This gene encodes a histone methyltransferase which functions in RNA polymerase II complexes by an interaction with a specific RNA helicase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMYD3 is a member of the SET and MYND‐domain family of lysine methyltransferases that is frequently overexpressed in a wide spectrum of human cancers—including colorectal, hepatocellular, breast, and rectal carcinomas. Its elevated expression correlates with malignant transformation and poor prognosis, as it promotes cell proliferation and survival through transcriptional reprogramming. In these tumors, increased levels of SMYD3 have been linked to enhanced growth, resistance to conventional therapies, and susceptibility to genetic alterations such as variable number tandem repeats that further increase its transcriptional activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, SMYD3 functions both as a chromatin modifier and a non‐histone methylator. It catalyzes methylation of histone H3 at lysine 4 and, in some contexts, histone H4 (including H4K5 and H4K20), thereby establishing activating epigenetic marks that augment transcription of oncogenic drivers. Moreover, SMYD3 is known to associate with RNA polymerase II and co‐activators—such as the RNA helicase HELZ, the cofactor PC4, and even select long noncoding RNAs—to directly regulate target genes including homeobox and cell‐cycle regulators (e.g. c‐Met, WNT10B, cyclins, and MMP9). In addition to these histone substrates, non‐histone targets are also methylated by SMYD3, enhancing key signal transduction cascades such as the Ras/Raf/MEK/ERK pathway (via MAP3K2 methylation), AKT1 activation, and even HER2 homodimerization. These coordinated actions facilitate cell migration, invasion, and overall tumor aggressiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBecause of its central role in reshaping the transcriptional landscape of cancer cells, SMYD3 represents an attractive therapeutic target. Pharmacological inhibition or RNA interference–mediated knockdown of SMYD3 significantly impairs tumor cell proliferation, invasiveness, and metastatic capabilities in preclinical models of colorectal, pancreatic, prostate, gastric, esophageal, and bladder cancers. SMYD3 activity is further implicated in modulating responses to oncogenic viruses (such as hepatitis B and C), in promoting epithelial–mesenchymal transition and in sustaining cancer stem cell traits via regulation of genes like ASCL2. In several studies, small‐molecule inhibitors (for example, BCI-121) that reduce SMYD3-mediated methylation have proven effective at reining in aberrant oncogenic signaling. These collective findings underscore the potential for SMYD3 to serve both as a prognostic biomarker and a therapeutic target in multiple malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ryuji Hamamoto, Yoichi Furukawa, Masashi Morita, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20811"}], "href": "https://doi.org/10.1002/gcc.20811"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20725992"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20725992"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Masataka Tsuge, Ryuji Hamamoto, Fabio Pittella Silva, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SMYD3 as an oncogenic driver in prostate cancer by stimulation of androgen receptor transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Natl Cancer Inst (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jnci/djt304"}], "href": "https://doi.org/10.1093/jnci/djt304"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24174655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24174655"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Claudio Fenizia, Cinzia Bottino, Silvia Corbetta, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Cooperation between SMYD3 and PC4 drives a distinct transcriptional program in cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkv874"}], "href": "https://doi.org/10.1093/nar/gkv874"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26350217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26350217"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Shutong Xu, Jian Wu, Bingfa Sun, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0197372"}], "href": "https://doi.org/10.1371/journal.pone.0197372"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29856759"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29856759"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Antonis Giakountis, Panagiotis Moulos, Michalis E Sarris, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SMYD3-Mediated H2A.Z.1 Methylation Promotes Cell Cycle and Cancer Proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-16-0500"}], "href": "https://doi.org/10.1158/0008-5472.CAN-16-0500"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27569210"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27569210"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Benjamin J Bernard, Nupur Nigam, Kyunghee Burkitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMYD3: a regulator of epigenetic and signaling pathways in cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Epigenetics (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13148-021-01021-9"}], "href": "https://doi.org/10.1186/s13148-021-01021-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33637115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33637115"}]}]}]}
Synonyms	BA74P14.1, ZMYND1, ZNFN3A1, KMT3E
Proteins	SMYD3_HUMAN
NCBI Gene ID	64754
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

SMYD3 has 14,578 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 134 datasets.

Click the + buttons to view associations for SMYD3 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

SMYD3 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of SMYD3 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of SMYD3 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of SMYD3 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of SMYD3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of SMYD3 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of SMYD3 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of SMYD3 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of SMYD3 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of SMYD3 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of SMYD3 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of SMYD3 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of SMYD3 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with SMYD3 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with SMYD3 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SMYD3 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of SMYD3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of SMYD3 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of SMYD3 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of SMYD3 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing SMYD3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing SMYD3 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing SMYD3 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with SMYD3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with SMYD3 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of SMYD3 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with SMYD3 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with SMYD3 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with SMYD3 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with SMYD3 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of SMYD3 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by SMYD3 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DGIdb Drug Targets 2026	interacting drugs for SMYD3 protein from the DGIdb Drug Targets 2026 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with SMYD3 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with SMYD3 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with SMYD3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with SMYD3 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with SMYD3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with SMYD3 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at SMYD3 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of SMYD3 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.