USP21 Gene

HGNC Family	Ubiquitin-specific peptidases (USP)
Name	ubiquitin specific peptidase 21
Description	This gene encodes a member of the C19 peptidase family, also known as family 2 of ubiquitin carboxy-terminal hydrolases. The encoded protein cleaves ubiquitin from ubiquitinated proteins for recycling in intracellular protein degradation. The encoded protein is also able to release NEDD8, a ubiquitin-like protein, from NEDD8-conjugated proteins. This gene has been referred to as USP16 and USP23 but is now known as USP21. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSP21 is a ubiquitin‐specific protease that modulates protein function by cleaving polyubiquitin chains. It displays a defined substrate selectivity by robustly hydrolyzing ubiquitin polymers and, with lower efficiency, targeting ISG15 while remaining inactive toward related modifiers such as NEDD8. Structural and saturation mutagenesis analyses have further revealed that USP21 engages its substrates via a previously unrecognized second binding surface and that cancer‐associated mutations can affect its nuclear export properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its catalytic activity, USP21 displays distinct subcellular localization patterns. It directly associates with centrosomes and microtubules via an N‐terminal binding motif, a feature that underpins its roles in reestablishing microtubule arrays after depolymerization, primary cilium formation, and even neurite outgrowth. Moreover, USP21 helps fine‐tune innate immune responses by deubiquitinating RIP1 to down‐regulate TNFα-induced NF‑κB signaling, by removing K27/K63-linked ubiquitin chains from STING to limit type I interferon production, and by stabilizing nuclear IL‑33 that supports NF‑κB p65–mediated transcription."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP21 also exerts critical nuclear functions by regulating the stability of key transcription factors. It deubiquitinates and stabilizes GATA3, thereby reinforcing regulatory T‑cell function, and similarly modulates the levels of FOXM1 and TCF/LEF family members to promote cell cycle progression and cancer stemness. In embryonic stem cells, USP21 preserves pluripotency through the stabilization of NANOG, and it has been shown to regulate developmental programs by deubiquitinating Goosecoid."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP21 has emerged as a multifaceted oncogenic regulator in a broad spectrum of cancers. Its deubiquitinating activity stabilizes MEK2 in hepatocellular and ovarian carcinomas, thereby enhancing ERK signaling, and it protects BRCA2 from proteasomal degradation to promote efficient homologous recombination. In renal cell carcinoma, USP21 fosters cancer stem cell properties by up-regulating IL‑8 transcription, while in glioblastoma and cervical cancer it stabilizes FOXD1 and FOXM1, respectively, contributing to mesenchymal identity and radio-resistance. Furthermore, transcriptional activation by factors such as SALL4 and modulation by long noncoding RNAs (e.g. LINC00174) underscore USP21’s role in esophageal, laryngeal, colorectal, and cholangiocarcinomas, with additional amplification noted in diffuse large B‑cell lymphoma and non‑small cell lung cancer through stabilization of oncogenic drivers like YY1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "24"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn light of its expansive influence on cell signaling, transcription, and DNA repair, USP21 is garnering attention as a promising therapeutic target. Small molecules such as disulfiram—and combinations with agents like 6‑thioguanine—have been shown to competitively inhibit USP21 activity, suggesting potential utility in cancer therapy. In parallel, USP21 has been implicated in the control of viral infections; by deubiquitinating the HIV‑1 transactivator Tat and reducing cyclin T1 expression, it effectively suppresses viral production. Collectively, these studies position USP21 as a central regulatory node whose modulation could yield therapeutic benefits across diverse pathological contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yu Ye, Masato Akutsu, Francisca Reyes-Turcu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biotechnol Appl Biochem (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/bab.2535"}], "href": "https://doi.org/10.1002/bab.2535"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37964466"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37964466"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Hsin-Cheng Lin, Ying Kuan, Hsu-Feng Chu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disulfiram and 6-Thioguanine synergistically inhibit the enzymatic activities of USP2 and USP21."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Macromol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ijbiomac.2021.02.072"}], "href": "https://doi.org/10.1016/j.ijbiomac.2021.02.072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33582217"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33582217"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Wenying Gao, Guangquan Li, Simin Zhao, et al. 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Synonyms	USP23, USP16
Proteins	UBP21_HUMAN
NCBI Gene ID	27005
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

USP21 has 5,537 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 106 datasets.

Click the + buttons to view associations for USP21 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

USP21 Gene

Functional Associations

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

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by USP21 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of USP21 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 USP21 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 USP21 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 USP21 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 USP21 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 USP21 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 USP21 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 USP21 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 USP21 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of USP21 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 USP21 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of USP21 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of USP21 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 USP21 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing USP21 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of USP21 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing USP21 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing USP21 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing USP21 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with USP21 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 USP21 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with USP21 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with USP21 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with USP21 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by USP21 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with USP21 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with USP21 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 USP21 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with USP21 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 USP21 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 USP21 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of USP21 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing USP21 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of USP21 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with USP21 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing USP21 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of USP21 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.
	GEO Signatures of Differentially Expressed Genes for Gene Perturbations	gene perturbations changing expression of USP21 gene from the GEO Signatures of Differentially Expressed Genes for Gene Perturbations dataset.
	GEO Signatures of Differentially Expressed Genes for Kinase Perturbations	kinase perturbations changing expression of USP21 gene from the GEO Signatures of Differentially Expressed Genes for Kinase Perturbations dataset.