RNF6 Gene

HGNC Family	Zinc fingers
Name	ring finger protein (C3H2C3 type) 6
Description	The protein encoded by this gene contains a RING-H2 finger motif. Deletions and mutations in this gene were detected in esophageal squamous cell carcinoma (ESCC), suggesting that this protein may be a potential tumor suppressor. Studies of the mouse counterpart suggested a role of this protein in the transcription regulation that controls germinal differentiation. Multiple alternatively spliced transcript variants encoding the same protein are observed. [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRNF6 plays a critical role during neuronal development by locally controlling actin dynamics. In primary hippocampal neurons, RNF6 binds, polyubiquitinates, and promotes the proteasomal degradation of LIM kinase 1 (LIMK1), thereby regulating axon outgrowth and growth cone dynamics during embryogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn colorectal cancer, RNF6 is frequently amplified and overexpressed, functioning as an oncogene by modulating several downstream targets. It ubiquitinates and degrades transcriptional repressors such as TLE3, thereby triggering Wnt/β-catenin activation, and promotes cell-cycle progression and epithelial‐to‐mesenchymal transition by targeting SHP‐1 for degradation, which in turn activates the JAK/STAT3 pathway. In addition, RNF6 can transcriptionally upregulate splicing factors like SF3B2, further contributing to tumor promotion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRNF6 also contributes to the pathogenesis of hematological malignancies. In leukemia, its overexpression, which is driven by the transcription factor PBX1, enhances cell proliferation. In multiple myeloma, RNF6 mediates atypical K63-linked polyubiquitination of the glucocorticoid receptor (GR), leading to increased receptor stability and transcriptional activity of downstream prosurvival genes, thereby conferring resistance to dexamethasone."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn breast cancer, RNF6 upregulation is associated with enhanced tumor cell proliferation and resistance to apoptosis. It promotes an oncogenic axis by upregulating and stabilizing estrogen receptor α (ERα), which in turn increases the expression of antiapoptotic factor Bcl-xL. Moreover, microRNA-26a-5p, which is downregulated in this cancer, directly targets the 3′UTR of RNF6 mRNA, and its loss further contributes to dysregulation of the RNF6/ERα/Bcl-xL pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hepatocellular carcinoma, elevated RNF6 expression correlates with a malignant phenotype, where it contributes to metastasis, the epithelial–mesenchymal transition, and even radioresistance. Mechanistically, RNF6 binds and ubiquitinates the transcription factor FoxA1, a key repressor of the EMT process. RNF6 overexpression in these tumors is also associated with poor patient survival, including in NAFLD-associated HCC."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn lung adenocarcinoma, RNF6 modulation affects DNA repair capacity and chemoresistance. Knockdown of RNF6 increases DNA double-strand breaks and enhances tumor cell sensitivity to cisplatin by reducing the transcription of PCNA—a key player in DNA repair—via diminished recruitment of TCF4 to its promoter."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cervical cancer, RNF6 overexpression promotes cell growth by activating the MAPK/ERK signaling pathway. Silencing RNF6 suppresses proliferation and induces apoptosis, suggesting its potential as a diagnostic and therapeutic target in this disease context."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSimilarly, in retinoblastoma, RNF6 is upregulated in drug-resistant cells. Its overexpression leads to resistance not only to carboplatin but also to other chemotherapeutic agents, via activation of the JAK2/STAT3 pathway, thereby underscoring its role as a biomarker and potential therapeutic target in overcoming drug resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic roles, RNF6 functions as an interferon-inducible E3 ubiquitin ligase that enhances antiviral responses. Elevated RNF6 levels in myeloid cells are correlated with increased interferon-stimulated gene expression in patients with systemic lupus erythematosus, highlighting a role in innate immunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRNF6 is also expressed in the testis, where it regulates genes essential for normal spermatogenesis. In mouse Sertoli cells, RNF6 binds to a specific DNA motif in the promoter of the inhibin α-subunit gene (Inha) and positively regulates its transcription, a function that may underlie its high expression in adult testis and its involvement in normal reproductive processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in mesenchymal stem cells, noncoding RNA LINC00707 promotes cell proliferation and reduces apoptosis by enhancing RNF6-mediated ubiquitination and subsequent degradation of the quaking protein (QKI), thereby impacting cell cycle progression and survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, recent studies and reviews underscore that RNF6—a RING-domain E3 ubiquitin ligase—functions through diverse mechanisms including targeted protein degradation, modulation of transcription factor stability, and alteration of key signaling pathways (such as Akt/mTOR, Wnt/β-catenin, and MAPK/ERK) to regulate neuronal development, tumorigenesis, chemoresistance, and immune responses. This multifaceted regulatory capacity positions RNF6 as a promising biomarker and therapeutic target across a range of physiological and pathological contexts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Baris Tursun, Anne Schlüter, Marvin A Peters, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1340605"}], "href": "https://doi.org/10.1101/gad.1340605"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16204183"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16204183"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Lei Liu, Yanquan Zhang, Chi Chun Wong, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "RING-Finger Protein 6 Amplification Activates JAK/STAT3 Pathway by Modifying SHP-1 Ubiquitylation and Associates with Poor Outcome in Colorectal Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-17-2133"}], "href": "https://doi.org/10.1158/1078-0432.CCR-17-2133"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29288235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29288235"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Qiken Li, Gang Wang, Jinhua Tao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNF6 promotes colorectal cancer invasion and migration via the Wnt/β-catenin pathway by inhibiting GSK3β activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Res Pract (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.prp.2021.153545"}], "href": "https://doi.org/10.1016/j.prp.2021.153545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34352441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34352441"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Hui Xu, Chi Chun Wong, Weilin Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RING-finger protein 6 promotes colorectal tumorigenesis by transcriptionally activating SF3B2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41388-021-01872-9"}], "href": "https://doi.org/10.1038/s41388-021-01872-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34611311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34611311"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xin Xu, Kunkun Han, Xiaowen Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M115.701979"}], "href": "https://doi.org/10.1074/jbc.M115.701979"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26971355"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26971355"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ying Ren, Xin Xu, Chen-Yu Mao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Pharmacol Sin (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41401-019-0309-6"}], "href": "https://doi.org/10.1038/s41401-019-0309-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31645658"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31645658"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Zi-Ming Huang, Heng-Fa Ge, Chen-Chen Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-26a-5p inhibits breast cancer cell growth by suppressing RNF6 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kaohsiung J Med Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/kjm2.12085"}], "href": "https://doi.org/10.1002/kjm2.12085"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31063232"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31063232"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yuanying Zeng, Xin Xu, Siyu Wang, et al. 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Proteins	RNF6_HUMAN
NCBI Gene ID	6049
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

RNF6 has 6,332 functional associations with biological entities spanning 8 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) extracted from 118 datasets.

Click the + buttons to view associations for RNF6 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 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 RNF6 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of RNF6 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 RNF6 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with RNF6 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with RNF6 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 RNF6 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of RNF6 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 RNF6 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 RNF6 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 RNF6 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing RNF6 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing RNF6 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing RNF6 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing RNF6 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 RNF6 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 RNF6 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 RNF6 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with RNF6 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with RNF6 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with RNF6 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of RNF6 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 RNF6 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with RNF6 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with RNF6 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 RNF6 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 RNF6 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with RNF6 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 RNF6 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 RNF6 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of RNF6 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 RNF6 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.