Affinage

ZNF263

Zinc finger protein 263 · UniProt O14978

Length
683 aa
Mass
77.3 kDa
Annotated
2026-06-11
17 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF263 is a C2H2 zinc finger transcription factor that binds defined promoter elements—including a 24-nucleotide ChIP-derived motif distinct from the zinc finger code prediction—to control gene expression in a context-dependent activator or repressor capacity (PMID:22130890, PMID:32051553, PMID:32277030). As a repressor, it occupies target promoters and recruits epigenetic silencing machinery: at SIX3 it engages the KAP1/HATS/DNMT corepressor complex to deposit H3K27me3 and DNA methylation, and at EGFR it recruits DNMT1 to drive promoter hypermethylation (PMID:32051553, PMID:38335093). As an activator, it directly transactivates a range of targets including RNF126, SMOX, CPT1B, and GPSM2, often in conjunction with cofactors such as OGT (PMID:38515383, PMID:42262434, PMID:39500874, PMID:37353617). Its activity is governed post-translationally: ERK downstream of EGFR-MAPK signaling binds ZNF263 and abrogates its ubiquitination to stabilize the protein (PMID:32051553), while OGT-mediated O-GlcNAcylation at Ser662 controls its chromatin association (PMID:37353617). Through these target programs ZNF263 acts as a regulator of cancer phenotypes—silencing tumor suppressors and activating oncogenic and metabolic targets across glioblastoma, lung, hepatocellular, pancreatic, and colorectal cancers (PMID:32051553, PMID:38335093, PMID:37353617, PMID:38515383, PMID:42262434)—and as a repressor of heparan sulfate biosynthesis genes (HS3ST1, HS3ST3A1), thereby shaping 3-O-sulfation and antithrombin binding (PMID:32277030). In human embryonic stem cells, ZNF263 initiates early differentiation genes while dampening the core pluripotency circuitry, with its loss impairing pluripotency dissolution and multi-lineage differentiation (PMID:41193435).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2012 Medium

    Defining the genuine DNA-binding preference of ZNF263 was needed because the zinc finger code prediction was unverified; experimental motif discovery established its true binding specificity.

    Evidence ChIP-seq with de novo motif discovery (ChIPMotifs)

    PMID:22130890

    Open questions at the time
    • No functional validation that the 24-nt motif drives target gene regulation
    • Does not establish whether binding is activating or repressive
  2. 2019 Medium

    Whether ZNF263 could act as a direct transcriptional activator was unresolved; binding and activation of the TORC2 promoter in bovine adipocytes demonstrated activator function at a defined core promoter region.

    Evidence Luciferase reporter with deletion/mutation, siRNA, EMSA in bovine adipocytes

    PMID:31487963

    Open questions at the time
    • Bovine system; relevance to human targets unclear
    • No cofactor or chromatin mechanism defined
  3. 2020 High

    How ZNF263 silences targets and how its own abundance is controlled were unknown; it was shown to recruit the KAP1/HATS/DNMT corepressor complex to the SIX3 promoter for epigenetic silencing, with ERK stabilizing ZNF263 by blocking its ubiquitination.

    Evidence Co-IP, ChIP, promoter methylation and ubiquitination assays in glioblastoma/astrocyte lines

    PMID:32051553

    Open questions at the time
    • Direct ERK phosphorylation sites on ZNF263 not mapped
    • Identity of the ubiquitin ligase not established
  4. 2020 High

    A physiological repressive program for ZNF263 outside cancer was undefined; loss-of-function showed it represses heparan sulfate biosynthesis genes, controlling 3-O-sulfation and antithrombin binding.

    Evidence CRISPR KO and siRNA with transcriptomics and biochemical HS functional assays across cell types

    PMID:32277030

    Open questions at the time
    • Corepressor machinery at HS gene promoters not characterized
    • Direct binding at individual HS3ST promoters not shown
  5. 2023 High

    The post-translational control of ZNF263 chromatin engagement was unknown; OGT-mediated O-GlcNAcylation at Ser662 was identified as required for its promoter association and cooperative transcriptional activation in HCC.

    Evidence ChIP-seq, Co-IP, Ser662 site-directed mutagenesis, in vitro/in vivo assays in HCC cells

    PMID:37353617

    Open questions at the time
    • Mechanism linking O-GlcNAcylation to DNA affinity not resolved
    • Whether modification switches activator vs repressor mode unknown
  6. 2024 High

    ZNF263's interplay with EGFR signaling was extended beyond its own stabilization; it represses EGFR transcription via DNMT1 recruitment and binds nuclear EGFR to disrupt EGFR-STAT5 signaling, modulating drug response.

    Evidence ChIP, Co-IP, promoter methylation, overexpression in LUAD lines and xenografts

    PMID:38335093

    Open questions at the time
    • Structural basis of ZNF263-nuclear EGFR interaction unknown
    • Reconciling activator vs repressor roles across tissues not addressed
  7. 2024 Medium

    Additional activating target programs were defined; ZNF263 activates CPT1B to enhance fatty acid oxidation and cisplatin resistance, and transactivates RNF126 (with ZNF31) to drive PTEN degradation and EMT.

    Evidence ChIP, luciferase, Co-IP, siRNA/overexpression in LUAD and PDAC, in vivo models

    PMID:38515383 PMID:39500874

    Open questions at the time
    • Cofactor requirements for these activations not fully defined
    • Single-lab studies with limited replication
  8. 2025 Medium

    A developmental role for ZNF263 was unestablished; it was shown to initiate early differentiation genes while dampening the pluripotency circuitry, with loss impairing pluripotency dissolution and lineage commitment.

    Evidence Genetic loss-of-function with differentiation assays and scRNA-seq in hESCs

    PMID:41193435

    Open questions at the time
    • Direct target genes in hESCs not mapped to binding events
    • Cofactors mediating activation vs repression in this context unknown
  9. 2026 Medium

    Further oncogenic activator targets were defined in colorectal cancer; ZNF263 activates SMOX to drive a ROS-TRIB3-GSK-3β-β-catenin metastatic axis and activates GPSM2 to promote cell cycle progression and invasion.

    Evidence ChIP-qPCR, Co-IP, luciferase, knockdown/overexpression in CRC lines, in vivo metastasis models

    PMID:41772960 PMID:42262434

    Open questions at the time
    • Whether the same chromatin/cofactor machinery operates at these promoters unknown
    • GPSM2 finding is single-lab with limited mechanistic depth

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what determines whether ZNF263 acts as an activator or repressor at a given promoter, and how its post-translational modifications and cofactor recruitment are integrated to select target programs across tissues.
  • No unified model linking O-GlcNAcylation, ERK stabilization, and cofactor choice
  • No structural model of ZNF263-DNA or ZNF263-cofactor complexes

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 2 R-HSA-1266738 Developmental Biology 1
Partners
DNMT1EGFRERKKAP1OGTZNF31
Complex memberships
KAP1/HATS/DNMT corepressor complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and DNA methylation of the SIX3 promoter. ERK, activated by EGFR-MAPK signaling, binds ZNF263 and abrogates its ubiquitination, leading to ZNF263 stabilization. Co-immunoprecipitation, chromatin immunoprecipitation, promoter methylation assays, ubiquitination assays, overexpression/knockdown in glioblastoma and astrocyte cell lines Oncogene High 32051553
2020 ZNF263 acts as a transcriptional repressor of heparin/heparan sulfate biosynthesis genes: CRISPR-mediated knockout and siRNA knockdown of ZNF263 in mammalian cell lines and primary human cells led to dramatically increased expression of HS3ST1 and HS3ST3A1, resulting in enhanced 3-O-sulfation and increased binding to antithrombin. ZNF263 binding motifs are enriched in promoter regions of heparin/heparan sulfate assembly genes. CRISPR knockout, siRNA knockdown, transcriptomics, biochemical heparan sulfate functional assays (antithrombin binding, Factor Xa inhibition, neuropilin-1 binding) in mammalian cell lines and primary human cells Proceedings of the National Academy of Sciences of the United States of America High 32277030
2024 ZNF263 binds the EGFR gene promoter and recruits DNMT1 to suppress EGFR transcription via DNA hypermethylation. ZNF263 also interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction and thereby enhancing AURKA expression, which improves response to osimertinib in lung adenocarcinoma. Chromatin immunoprecipitation, co-immunoprecipitation, promoter methylation assays, overexpression in LUAD cell lines, xenograft animal models with lentivirus/AAV-mediated ZNF263 overexpression Cell reports High 38335093
2023 OGT-mediated O-GlcNAcylation of ZNF263 at Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters in hepatocellular carcinoma cells. ZNF263 cooperates with OGT to activate downstream transcription that promotes HCC malignant progression. ChIP-seq, co-immunoprecipitation, site-directed mutagenesis (Ser662), in vitro and in vivo functional assays in HCC cells Oncogene High 37353617
2024 ZNF263 directly binds the promoter of CPT1B to activate its transcription, enhancing fatty acid β-oxidation (FAO) and promoting cisplatin resistance in lung adenocarcinoma cells. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, FAO rate measurement, IC50 assays in LUAD cell lines The pharmacogenomics journal Medium 39500874
2024 ZNF263 transactivates RNF126 by binding to its promoter; ZNF263 interacts with ZNF31 to co-regulate RNF126 transcription. RNF126 in turn promotes ubiquitination-mediated degradation of PTEN, activating AKT/Cyclin D1 and AKT/GSK-3β/β-catenin signaling to drive EMT and drug resistance in pancreatic cancer. Chromatin immunoprecipitation, co-immunoprecipitation, luciferase reporter assay, siRNA/overexpression in PDAC cell lines, xenograft and liver metastasis models in vivo Journal of cellular physiology Medium 38515383
2019 ZNF263 acts as a transcriptional activator of the TORC2 gene promoter in bovine adipocytes, binding within the core promoter region (-314 to -69 bp upstream of TSS). Luciferase reporter assay with serial deletion and site-specific mutants, siRNA knockdown, Electrophoretic Mobility Shift Assay (EMSA) with nuclear extracts from bovine adipocytes International journal of molecular sciences Medium 31487963
2021 ZNF263 binds to an intronic region of COL4A3 in bronchial epithelium, as demonstrated by chromatin immunoprecipitation sequencing (ChIP-seq), and ZNF263 silencing by siRNA alters COL4A3 expression. ChIP-seq coupled with qPCR, siRNA knockdown, DNA methylation bead arrays, RNA-sequencing in human bronchial biopsies and cell lines ERJ open research Medium 34109240
2025 ZNF263 directly initiates expression of early differentiation genes and concurrently dampens the core pluripotency circuitry in human embryonic stem cells. ZNF263 deficiency impairs pluripotency dissolution and multi-lineage differentiation (particularly toward ectoderm), as shown by genetic loss-of-function and single-cell transcriptomic profiling. Genetic knockout/knockdown, functional differentiation assays, single-cell RNA sequencing in hESCs Nature communications Medium 41193435
2023 ZNF263 overexpression in BEAS-2B cells inhibits CSE-induced cellular senescence and SASP factor secretion by upregulating klotho expression, placing ZNF263 upstream of klotho in this pathway. ZNF263 overexpression in BEAS-2B cells, Western blot, ELISA for senescence markers and SASP factors, qPCR for klotho transcription International journal of chronic obstructive pulmonary disease Low 37065635
2012 De novo motif discovery using ChIP-based high-throughput data established that ZNF263 binds a 24-nucleotide site that differs from the motif predicted by the zinc finger code in several positions. ChIP-seq combined with de novo motif discovery (ChIPMotifs: MEME, MaMF, Weeder with bootstrap re-sampling and Fisher test) Methods in molecular biology Medium 22130890
2026 ZNF263 directly binds the SMOX promoter and transcriptionally activates SMOX expression in colorectal cancer cells, driving a ZNF263-SMOX-ROS-TRIB3-GSK-3β-β-catenin signaling axis that promotes CRC metastasis. ChIP-qPCR, Co-IP, Western blotting, knockdown/overexpression functional assays in CRC cell lines, xenograft and peritoneal metastasis models in vivo Apoptosis Medium 42262434
2026 ZNF263 acts as a transcriptional activator of GPSM2 in colorectal cancer cells, binding the GPSM2 promoter and activating the cell cycle pathway in a GPSM2-dependent manner to promote CRC cell invasion, migration, and proliferation. Chromatin immunoprecipitation, luciferase reporter assay, siRNA/overexpression in CRC cell lines, functional proliferation/invasion/migration assays Acta biochimica et biophysica Sinica Low 41772960
2023 ZNF263 binds to the NPPB gene promoter at the rs3753581 (-1299G) variant site and is involved in regulation of NPPB transcription, as validated by chromatin immunoprecipitation and luciferase reporter assays. Chromatin immunoprecipitation, luciferase reporter assay, bioinformatics prediction (TESS), genotyping in clinical cohort Gene Low 37339722

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Function and Transcriptional Regulation of Bovine TORC2 Gene in Adipocytes: Roles of C/EBP, XBP1, INSM1 and ZNF263. International journal of molecular sciences 42 31487963
2020 The EGFR-ZNF263 signaling axis silences SIX3 in glioblastoma epigenetically. Oncogene 35 32051553
2020 ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 32 32277030
2015 High cortisol in 5-year-old children causes loss of DNA methylation in SINE retrotransposons: a possible role for ZNF263 in stress-related diseases. Clinical epigenetics 32 26339299
2020 A zinc finger family protein, ZNF263, promotes hepatocellular carcinoma resistance to apoptosis via activation of ER stress-dependent autophagy. Translational oncology 31 32898766
2024 Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma. Cell reports 25 38335093
2021 Circular RNA FOXP1 Induced by ZNF263 Upregulates U2AF2 Expression to Accelerate Renal Cell Carcinoma Tumorigenesis and Warburg Effect through Sponging miR-423-5p. Journal of immunology research 21 34514002
2023 Chromatin-associated OGT promotes the malignant progression of hepatocellular carcinoma by activating ZNF263. Oncogene 12 37353617
2024 ZNF263 cooperates with ZNF31 to promote the drug resistance and EMT of pancreatic cancer through transactivating RNF126. Journal of cellular physiology 9 38515383
2021 COL4A3 expression in asthmatic epithelium depends on intronic methylation and ZNF263 binding. ERJ open research 8 34109240
2024 The ZNF263/CPT1B axis regulates fatty acid β-oxidation to affect cisplatin resistance in lung adenocarcinoma. The pharmacogenomics journal 6 39500874
2012 Using ChIPMotifs for de novo motif discovery of OCT4 and ZNF263 based on ChIP-based high-throughput experiments. Methods in molecular biology (Clifton, N.J.) 4 22130890
2023 Bufei Yishen Formula Inhibits the Cell Senescence in COPD by Up-Regulating the ZNF263 and Klotho Expression. International journal of chronic obstructive pulmonary disease 2 37065635
2026 Transcriptional regulation of GPSM2 by ZNF263 in colorectal cancer: implications for tumor aggressiveness. Acta biochimica et biophysica Sinica 0 41772960
2026 A novel ZNF263-SMOX-ROS-TRIB3 signaling axis drives Wnt/β-catenin activation and metastatic progression in colorectal cancer. Apoptosis : an international journal on programmed cell death 0 42262434
2025 Transcription factor ZNF263 primes human embryonic stem cells for pluripotency dissolution and lineage commitment. Nature communications 0 41193435
2023 The underlying mechanism of transcription factor IRF1, PRDM1, and ZNF263 involved in the regulation of NPPB rs3753581 on pulse pressure hypertension. Gene 0 37339722

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