Affinage

CBX4

E3 SUMO-protein ligase CBX4 · UniProt O00257

Length
560 aa
Mass
61.4 kDa
Annotated
2026-06-09
75 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBX4 is a dual-function polycomb group protein that controls gene silencing, DNA repair, cellular senescence, metabolism, and immune regulation by combining chromatin reader/repressor activity with a SUMO E3 ligase function (PMID:24434214, PMID:21885019, PMID:41915438). As a chromodomain-containing component of canonical PRC1, CBX4 represses target loci by maintaining inhibitory H2AK119ub1 and H3K27me3 marks; a CBX4/PCGF4-containing cPRC1 species accumulates at H3K27me3-enriched CpG islands and is required for oncogenic repression in diffuse midline glioma, and this same PRC1-dependent silencing extends to endogenous retroelements, whose derepression upon CBX4 loss triggers cytosolic RNA sensing and a type I interferon response (PMID:40403727, PMID:41915438, PMID:37691307). Independently of its chromodomain, CBX4 functions as a SUMO E3 ligase that depends on two SUMO-interacting motifs (SIMs) for full activity, its own sumoylation, and SUMO enrichment at polycomb bodies (PMID:20098713, PMID:24434214). Through this activity CBX4 sumoylates a broad substrate set — HIF-1α to enhance angiogenic transcription (PMID:24434214, PMID:40478492), BMI1 and CtIP at DNA lesions to promote DNA-damage recruitment, end resection, and homologous recombination (PMID:22402492, PMID:28740167), and Prdm16, hTERT, YAP1, BRD4, and SP1/KLF3 to modulate substrate stability, transcriptional output, or signaling in metabolism, EMT, inflammation, and T-cell function (PMID:29539416, PMID:32926159, PMID:39154499, PMID:39349832, PMID:38994031). CBX4 also acts non-catalytically as a transcriptional scaffold, recruiting histone-modifying enzymes such as HDAC3, HDAC1, and GCN5 to target promoters to repress or activate genes including Runx2, KLF6, and PHGDH (PMID:27864346, PMID:32113161, PMID:32111827, PMID:38816356). CBX4 abundance and ligase activity are tightly regulated: CK1α-mediated T437 phosphorylation drives CHIP-dependent ubiquitination and proteasomal degradation (PMID:32111827), K106 acetoacetylation lowers E3 ligase activity (PMID:41045931), SALL1 binding reduces CBX4 ubiquitination and expands polycomb bodies (PMID:34621739), and CUL4A-dependent ubiquitination targets CBX4 for degradation (PMID:39692477). In immune cells CBX4 restrains effector function by silencing Pdcd1 (PD-1) through PRC1/PRC2 marks and by sumoylating SP1/KLF3 to suppress CD8+ T-cell glycolysis, linking it to anti-tumor immunity and checkpoint therapy response (PMID:37691307, PMID:38994031, PMID:41915438).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2007 High

    Established that CBX4 functions as a SUMO E3 ligase toward a sequence-specific chromatin regulator, defining a catalytic role distinct from passive chromatin reading.

    Evidence Co-IP, cellular co-expression, and in vitro sumoylation with purified CBX4 on Dnmt3a

    PMID:17439403

    Open questions at the time
    • Functional consequence of Dnmt3a sumoylation on its methyltransferase activity not resolved
    • SUMO acceptor lysine not pinpointed
  2. 2010 Medium

    Defined the molecular basis of CBX4 ligase activity by showing two SUMO-interacting motifs are required for substrate sumoylation, autosumoylation, and SUMO concentration at polycomb bodies.

    Evidence SIM mutagenesis with cell-based sumoylation assays and immunofluorescence of polycomb foci

    PMID:20098713

    Open questions at the time
    • Structural basis of SIM-SUMO recognition not solved
    • Substrate specificity determinants beyond SIMs unknown
  3. 2012 High

    Showed CBX4 has a direct genome-protective role by relocalizing to DNA damage in a PARP-dependent pathway and sumoylating BMI1 to promote its accumulation at lesions.

    Evidence Laser micro-irradiation, live imaging, in vitro SUMO conjugation, and BMI1 K88 mutagenesis with radiation-resistance readout

    PMID:22402492

    Open questions at the time
    • Mechanism of PARP-dependent CBX4 recruitment unknown
    • Whether BMI1 sumoylation alone accounts for repair phenotype not isolated
  4. 2017 High

    Identified CtIP as a CBX4 SUMO substrate whose modification is essential for DNA end resection and homologous recombination, mechanistically linking CBX4 to genome stability.

    Evidence siRNA depletion, CtIP K896R mutagenesis, SUMO-CtIP fusion rescue, resection and HR reporter assays

    PMID:28740167

    Open questions at the time
    • How CtIP sumoylation drives recruitment mechanistically not detailed
    • Interplay with the BMI1 DNA-damage pathway not addressed
  5. 2011 High

    Separated CBX4's two activities functionally, showing the chromodomain mediates anti-senescence while the SUMO ligase controls stem cell activation in epidermal stem cells.

    Evidence Domain-specific mutagenesis with transcriptome, ChIP, senescence and differentiation assays

    PMID:21885019

    Open questions at the time
    • Direct chromatin targets driving anti-senescence not fully defined
    • SUMO substrates underlying the differentiation phenotype not identified
  6. 2013 High

    Established CBX4 as a non-redundant developmental regulator via interaction with p63 in thymic epithelium required for T-cell development.

    Evidence Conditional and conventional Cbx4 knockout mice, CBX4-p63 co-IP, histology, and T-cell flow cytometry

    PMID:23362346

    Open questions at the time
    • Whether CBX4 catalytic or reader activity drives the TEC phenotype not separated
    • Direct CBX4 target genes in TECs unknown
  7. 2016 High

    Revealed a SUMO- and PRC1-independent repressive mode in which CBX4 recruits HDAC3 to suppress Runx2 and limit metastasis.

    Evidence Reciprocal co-IP, ChIP at Runx2 promoter, domain mutagenesis, and in vivo metastasis models

    PMID:27864346

    Open questions at the time
    • Domain of CBX4 mediating HDAC3 binding not mapped
    • Reconciliation with later Runx2 activation via GCN5 not addressed
  8. 2018 High

    Demonstrated that CBX4 sumoylation can stabilize substrates against degradation, sumoylating Prdm16 to drive adipose thermogenic programs in vivo.

    Evidence In vivo SUMO ligase assay, Prdm16 K917R mutagenesis, stability assays, and adipose-specific Cbx4 mouse models

    PMID:29539416

    Open questions at the time
    • Mechanism by which sumoylation blocks Prdm16 ubiquitination not defined
    • Upstream signals controlling CBX4 in adipose tissue unknown
  9. 2019 High

    Linked CBX4 to nucleolar heterochromatin maintenance and aging by recruiting FBL and KAP1 to rDNA to limit rRNA synthesis and senescence.

    Evidence CBX4 KO in hMSCs, ChIP for CBX4/FBL/KAP1 at rDNA, ribosome/translation assays, and in vivo rescue

    PMID:30917318

    Open questions at the time
    • How CBX4 is targeted to rDNA not resolved
    • Whether catalytic or reader activity drives nucleolar function not separated
  10. 2020 High

    Defined post-translational control of CBX4 stability, showing CK1α phosphorylation at T437 promotes CHIP-mediated ubiquitination and degradation, with CBX4 promoting Runx2 via GCN5 recruitment.

    Evidence T437A and ubiquitination-site mutagenesis, CBX4-CHIP co-IP, CK1α activator treatment, and ChIP for GCN5

    PMID:32111827

    Open questions at the time
    • Reconciliation of CBX4 activating vs repressing Runx2 across cancer types unresolved
    • Physiological signals upstream of CK1α control incompletely mapped
  11. 2020 Medium

    Extended the CBX4 sumoylation substrate set to hTERT and demonstrated a transcriptional-scaffold role with HDAC1, connecting CBX4 to telomerase activity, EMT, and renal cancer growth.

    Evidence Co-IP, in-cell sumoylation, SUMO-defective hTERT mutant, telomerase and ChIP assays (hTERT/ZEB1; KLF6 with HDAC1)

    PMID:32113161 PMID:32926159

    Open questions at the time
    • Single-lab findings without reciprocal validation across contexts
    • Whether hTERT sumoylation and HDAC1 recruitment occur in the same complex unknown
  12. 2024 Medium

    Expanded the CBX4 SUMO substrate network into Hippo signaling, BRD4-driven inflammation, and T-cell metabolism, and added genome-wide chromatin scaffold functions, mapping CBX4 to chemoresistance, immune, and metabolic programs.

    Evidence Site-specific sumoylation mutagenesis (YAP1, BRD4), ChIP-seq/RNA-seq (PHGDH, ZEB2), CBX4 KO mice and ChIP-seq for SP1/KLF3-Aldob axis

    PMID:38816356 PMID:38994031 PMID:39154499 PMID:39349832

    Open questions at the time
    • Each substrate axis established in a single context/lab
    • How CBX4 selects between sumoylation and PRC1 scaffold modes per locus unknown
  13. 2024 Medium

    Identified additional regulators of CBX4 abundance — SALL1 stabilizing it and CUL4A targeting it for degradation — and K106 acetoacetylation as a metabolic brake on its ligase activity.

    Evidence Co-IP, ubiquitination assays, polycomb-body imaging (SALL1), CUL4A co-IP with ChIP at HIV LTR, and K106 mutagenesis with in vitro ligase assay

    PMID:34621739 PMID:39692477 PMID:41045931

    Open questions at the time
    • Interplay among the multiple CBX4 degradation pathways not integrated
    • Physiological triggers of acetoacetylation beyond HADH activation unclear
  14. 2025 High

    Established CBX4 as a silencer of endogenous retroelements whose loss activates innate immune sensing, and a CBX4/PCGF4-cPRC1 species as essential for oncogenic repression, defining its tumor-immune and chromatin-targeting roles.

    Evidence In vivo CRISPR screens, ChIP for H3K9me3/H3K27me3 at retroelements, IFN assays (retroelement silencing); CRISPR screens, CBX4-PCGF4 co-IP and ChIP-seq with domain mutagenesis (DMG)

    PMID:40403727 PMID:41915438

    Open questions at the time
    • How CBX4 distinguishes retroelement from gene targets not defined
    • Function of the central disordered region beyond PCGF4 association not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CBX4 partitions between its PRC1 chromatin-reader role, its SUMO E3 ligase activity, and its catalytic-independent HDAC/GCN5 scaffold function at any given locus, and what determines substrate and target selection, remains unresolved.
  • No structural model integrating chromodomain, SIM, and disordered regions in substrate/target choice
  • No unifying account of why CBX4 represses some genes and activates others
  • Context-dependence of opposing tumor-suppressive vs oncogenic outcomes not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0140110 transcription regulator activity 5 GO:0016740 transferase activity 4 GO:0060090 molecular adaptor activity 4 GO:0016874 ligase activity 3 GO:0042393 histone binding 3
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-4839726 Chromatin organization 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-162582 Signal Transduction 2 R-HSA-73894 DNA Repair 2
Partners
BMI1CTIPGCN5HDAC3HIF-1ΑP63PCGF4PRDM16
Complex memberships
canonical PRC1 (CBX4/PCGF4-containing)polycomb bodies

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 CBX4 acts as a SUMO E3 ligase for HIF-1α, enhancing its sumoylation at K391 and K477 via two SUMO-interacting motif (SIM)-dependent mechanisms, which increases HIF-1 transcriptional activity and promotes VEGF expression and angiogenesis in hepatocellular carcinoma cells. In vitro sumoylation assay, co-immunoprecipitation, mutagenesis of HIF-1α sumoylation sites, SUMO-interacting motif mutation, VEGF/angiogenesis readouts in cell and mouse HCC models Cancer Cell High 24434214
2012 CBX4 localizes to sites of DNA damage (laser micro-irradiation) in a PARP-dependent but H2AX-, RNF8-, BMI1-, and PI-3K-independent manner, where it acts as a SUMO E3 ligase to sumoylate BMI1 at lysine 88, promoting BMI1 accumulation at DNA lesions and cellular resistance to ionizing radiation. Laser micro-irradiation, live-cell imaging, co-immunoprecipitation, in vitro SUMO conjugation assay, siRNA depletion, mutagenesis of BMI1 K88 Nucleic Acids Research High 22402492
2007 CBX4 physically interacts with Dnmt3a and promotes its SUMOylation with SUMO-1 in the N-terminal regulatory/PWWP domain region, functioning as a SUMO E3 ligase for Dnmt3a in cells and in vitro. Co-immunoprecipitation, co-expression in transfected cells, purified protein in vitro SUMOylation assay Biochemical Journal High 17439403
2010 CBX4/Pc2 contains two functional SUMO-interacting motifs (SIMs) that are required for its full SUMO E3 ligase activity in mammalian cells, for its own sumoylation, for CBX4-dependent sumoylation of CtBP, and for enrichment of SUMO1/SUMO2 at polycomb bodies. SIM-interacting residues of both SUMO1 and SUMO2 are also required for Pc2-mediated sumoylation. SIM mutagenesis, cell-based sumoylation assay, immunofluorescence of polycomb foci, SUMO1/SUMO2 surface mutagenesis PLoS ONE Medium 20098713
2017 CBX4 acts as the SUMO E3 ligase for CtIP, promoting its constitutive sumoylation at K896; this sumoylation is essential for CtIP recruitment to DNA double-strand breaks, DNA end resection, and homologous recombination. Mutation of K896 or CBX4 depletion blocks resection and increases genomic instability. Artificial SUMO–CtIP fusion suppresses both phenotypes. siRNA depletion, K896R mutagenesis, SUMO–CtIP fusion rescue, resection assay, HR reporter assay, co-immunoprecipitation, genomic instability measurement Nature Communications High 28740167
2011 In human epidermal stem cells, the polycomb (chromodomain) activity of CBX4 is required for its anti-senescence function but not for preventing stem cell differentiation, whereas its SUMO E3 ligase activity inhibits stem cell activation and differentiation. CBX4 represses Ezh2, Dnmt1, and Bmi1 transcription as assessed by chromatin occupancy and transcriptome analysis. Polycomb domain and SUMO ligase mutagenesis/abrogation, transcriptome analysis, chromatin immunoprecipitation, senescence and differentiation assays Cell Stem Cell High 21885019
2015 In developing stratified epithelium, CBX4 chromodomain-dependent and SUMO E3 ligase-dependent activities differentially regulate keratinocyte proliferation, differentiation, and repression of nonepidermal lineage genes. CBX4 expression in keratinocytes is directly regulated by p63, and CBX4 overexpression partially rescues p63 ablation effects on epidermal development. Cbx4 ablation in mice, domain-specific mutagenesis (chromodomain and SUMO ligase mutants), ChIP for p63 at Cbx4 promoter, rescue experiments, histology and proliferation assays Journal of Cell Biology High 26711500
2013 CBX4 physically interacts with the transcription factor p63 in thymic epithelial cells; Cbx4-deficient TECs show impaired proliferative capacity and failure of thymic architecture, and T-cell development is severely blocked, establishing CBX4 as a non-redundant regulator of thymic epithelium maintenance. Conditional and conventional Cbx4 knockout in mice, co-immunoprecipitation of CBX4–p63 interaction, histology, flow cytometry of T-cell populations Development High 23362346
2018 CBX4 is a SUMO E3 ligase for Prdm16, sumoylating it at K917; this sumoylation blocks Prdm16 ubiquitination-mediated degradation, stabilizes Prdm16 protein, and is required for thermogenic gene expression in brown/beige adipose tissue. Heterozygous Cbx4-knockout mice develop metabolic phenotypes resembling Prdm16-knockout mice. In vivo SUMO E3 ligase assay, K917R mutagenesis of Prdm16, co-immunoprecipitation, protein stability assays, adipose-specific Cbx4 KO/OE mouse models, thermogenic gene expression Cell Reports High 29539416
2016 CBX4 suppresses colorectal carcinoma metastasis by repressing Runx2 transcription through physically recruiting HDAC3 to the Runx2 promoter, maintaining a deacetylated H3K27 state. This function requires the CBX4–HDAC3 interaction but is independent of its SUMO E3 ligase activity, chromodomain, and PRC1 complex. Co-immunoprecipitation of CBX4–HDAC3, chromatin immunoprecipitation, domain mutagenesis, cell migration/invasion assays, in vivo metastasis models Cancer Research High 27864346
2019 CBX4 maintains nucleolar homeostasis in human mesenchymal stem cells by recruiting fibrillarin (FBL) and KAP1 to nucleolar rDNA, limiting rRNA expression. CBX4 knockout destabilizes nucleolar heterochromatin, enhances ribosome biogenesis and protein translation, and accelerates cellular senescence; CBX4 overexpression alleviates physiological hMSC aging. CBX4 knockout in hMSCs, co-immunoprecipitation and recruitment assays at rDNA (ChIP), ribosome biogenesis and translation assays, senescence assays, osteoarthritis mouse model Cell Reports High 30917318
2020 Phosphorylation of CBX4 at T437 by CK1α facilitates its ubiquitination at K178 and K280 by the E3 ligase CHIP, leading to its proteasomal degradation; TNFα reduces this CK1α-mediated phosphorylation, thereby stabilizing CBX4. CK1α inhibits osteosarcoma metastasis through inhibition of CBX4. CBX4 promotes metastasis by transcriptionally upregulating Runx2 via recruitment of GCN5 to the Runx2 promoter. Phosphorylation site mutagenesis (T437A), ubiquitination assay, co-immunoprecipitation of CBX4–CHIP, CK1α activator (pyrvinium pamoate) treatment, ChIP for GCN5 at Runx2 promoter, migration/invasion assays Nature Communications High 32111827
2020 CBX4 acts as SUMO E3 ligase for hTERT, promoting its SUMO1 modification; hTERT SUMOylation positively regulates telomerase activity (reversible by SENP3) and promotes retention of the hTERT/ZEB1 complex on the E-cadherin promoter, leading to E-cadherin repression and EMT in breast cancer cells. Co-immunoprecipitation of CBX4–hTERT, in cell sumoylation assay, SUMO-defective hTERT mutant, telomerase activity assay, SENP3 de-SUMOylation, ChIP for hTERT/ZEB1 at CDH1 promoter, wound healing/invasion assay Biochemical Journal Medium 32926159
2017 CBX4 acts as a ubiquitin E3 ligase for HDAC7 in the dorsal hippocampus, promoting its ubiquitin-dependent degradation after contextual fear conditioning; this reduces HDAC7 levels, allows upregulation of the target gene Nur77, and is required for long-term contextual fear memory formation. Co-immunoprecipitation of CBX4–HDAC7, ubiquitination assay, in vivo hippocampal injection, contextual fear conditioning behavioral assay, HDAC7 protein stability analysis Journal of Neuroscience Medium 28283560
2020 CBX4 physically interacts with HDAC1 and recruits it to the KLF6 promoter, transcriptionally suppressing KLF6 expression in clear cell renal cell carcinoma; disruption of the CBX4–HDAC1 interaction attenuates CBX4-mediated cell growth and migration. Co-immunoprecipitation of CBX4–HDAC1, chromatin immunoprecipitation at KLF6 promoter, CBX4 knockdown/overexpression, interaction-disrupting domain analysis, in vitro and in vivo tumor models EBioMedicine Medium 32113161
2019 CBX4 in breast cancer cells suppresses miR-137 promoter activity in a PRC1-dependent manner; reduced miR-137 then increases Notch1 signaling (via upregulation of Notch1, Jag1, Hey2), promoting tumor growth and migration. CBX4 overexpression/knockdown, miR-137 promoter luciferase reporter, 3'-UTR luciferase assays for Notch1/Jag1/Hey2, siRNA rescue experiments, cell growth and migration assays International Journal of Biochemistry & Cell Biology Medium 29229426
2022 CBX4 acts as a SUMO E3 ligase for the transcription factor TFII-I, enhancing TFII-I SUMOylation to promote MEX-3B transcription; MEX-3B then binds lfTSLP mRNA through its K homology domains to enhance its translation, increasing long-form TSLP expression and airway inflammation in asthma. Co-immunoprecipitation, sumoylation assay, MEX-3B mRNA binding (RNA immunoprecipitation), promoter analysis, CBX4 inhibitor treatment in mouse asthma model American Journal of Respiratory Cell and Molecular Biology Medium 35358396
2024 CBX4 sumoylates YAP1 at K97 and K280 (SUMO1 modification), which competitively inhibits YAP1-S127 phosphorylation, preserving YAP1 stability and its cytoplasm-to-nucleus transport, thereby deactivating the Hippo pathway senescence response and conferring chemoresistance in gastric cancer. Low-dose cisplatin transcriptionally downregulates CBX4 via CEBPB. Co-immunoprecipitation, SUMO modification site mutagenesis (K97R/K280R), phosphorylation analysis of YAP1-S127, ChIP for CEBPB at CBX4 promoter, in vitro and in vivo chemoresistance assays Drug Resistance Updates Medium 39154499
2024 CBX4 sumoylates BRD4 at K1111, preventing its ubiquitin-mediated degradation and thereby activating BRD4-dependent transcription of IL-1β, TNF-α, and IL-6 in synovial fibroblasts; SUMOylated BRD4 also recruits TRMT112 to further enhance proinflammatory gene expression. Co-immunoprecipitation of CBX4–BRD4, in-cell sumoylation assay, K1111 mutagenesis, BRD4 ubiquitination/stability assay, TRMT112 interaction, Cbx4 inhibitor in rat PTOA model Experimental & Molecular Medicine Medium 39349832
2024 CBX4 sumoylates SP1 and KLF3 in CD8+ T cells, increasing expression of aldolase B (Aldob); Aldob inhibits glycolysis and ATP synthesis by reducing Akt phosphorylation, suppressing CD8+ T cell effector function. CBX4 knockout enhances CD8+ T cell glycolysis, function, and anti-PD-1 therapy efficacy. T cell-specific CBX4 KO mice, flow cytometry, Cut-Tag qPCR, ChIP-seq, immunoprecipitation, metabolite detection, sumoylation assay, adoptive T cell transfer Theranostics Medium 38994031
2023 CBX4 suppresses PD-1 (Pdcd1) expression in T cells by maintaining inhibitory histone marks H2AK119ub1 and H3K27me3 at the Pdcd1 promoter (at CR-C and CR-B sites) via PRC1 E3 ligase and PRC2 methyltransferase activities; T cell-specific Cbx4 deletion increases PD-1 levels and impairs effector T cell function. T cell-specific Cbx4 knockout mice, epigenetic ChIP (H2AK119ub1, H3K27me3 at Pdcd1 locus), PRC1/PRC2 inhibitors, CBX4 overexpression, flow cytometry for T cell phenotypes Molecular Oncology Medium 37691307
2025 CBX4 acetoacetylation at K106 (promoted by HADH-driven acetoacetyl-CoA accumulation) reduces its SUMO E3 ligase activity, thereby diminishing HIF-1α sumoylation and transcriptional activity in hepatocellular carcinoma cells. Phenotypic compound screen, HADH activation assay, acetoacetyl-CoA measurement, K106 mutagenesis, in vitro SUMO E3 ligase assay, CBX4-overexpressing xenograft model Cell Chemical Biology Medium 41045931
2021 SALL1 interacts with CBX4 in the nucleoplasm and reduces CBX4 ubiquitination, enhancing its stability; increased SALL1 expression expands the number and size of CBX4-containing Polycomb bodies and increases repression of CBX4 target genes. Co-immunoprecipitation of SALL1–CBX4, ubiquitination assay, immunofluorescence of polycomb bodies, target gene expression analysis Frontiers in Cell and Developmental Biology Medium 34621739
2024 CBX4 promotes lung adenocarcinoma cell proliferation by interacting with GCN5 to induce histone acetylation at the PHGDH promoter, upregulating PHGDH expression and serine biosynthesis; CBX4 simultaneously suppresses metastasis by recruiting canonical PRC1 to establish H2AK119ub at the ZEB2 promoter and inhibiting ZEB2 transcription. ChIP-seq and RNA-seq, co-immunoprecipitation of CBX4–GCN5, chromatin immunoprecipitation at PHGDH and ZEB2 promoters, CBX4 KD/OE in vitro and in vivo models Cell Death & Disease Medium 38816356
2025 A specific form of canonical PRC1 containing CBX4 and PCGF4 drives oncogenic gene repression downstream of H3K27me3 in diffuse midline glioma (DMG) cells. Via a novel functional central disordered region, CBX4 preferentially associates with PCGF4-containing cPRC1. The characteristic DMG H3K27me3 landscape rewires cPRC1 complex distribution, causing CBX4/PCGF4-cPRC1 to accumulate at H3K27me3-enriched CpG islands. Despite comprising <5% of total cPRC1, this complex is essential for DMG growth. Genome-wide and tiling-scan CRISPR screens, co-immunoprecipitation of CBX4–PCGF4, ChIP-seq for H3K27me3 and cPRC1 distribution, domain functional mutagenesis, DMG cell growth assays Molecular Cell High 40403727
2023 CBX4 deletion promotes genomic instability (chromosomal instability) in KrasG12D-mutated mouse embryonic fibroblasts, upregulates p15, p16, and apoptosis-related genes, and paradoxically selects for cells with increased proliferative and transformation abilities, enabling lung adenocarcinoma progression via altered Hippo pathway signaling. Conditional Cbx4/KrasG12D mouse model, Cre-mediated deletion, karyotype analysis, RNA-seq, apoptosis assays, tumor progression in vivo Signal Transduction and Targeted Therapy Medium 37696812
2022 CBX4 binds to the CDC20 promoter in coordination with H3K4me3 and activates CDC20 mRNA expression in gastric cancer cells, promoting cancer stemness and proliferation in a CDC20-dependent manner. ChIP-qPCR at CDC20 promoter, CBX4 knockdown/overexpression, sphere formation (stemness) and proliferation assays Journal of Gastrointestinal Oncology Low 35837165
2022 CBX4 stabilizes nuclear localization of HDAC3 in craniopharyngioma cells, suppressing Bmp2-induced osteoblastic differentiation and calcification; miR-181b targets CBX4 to reduce its expression and release HDAC3 from nuclear retention, enabling Runx2 activation. Luciferase reporter assay (miR-181b–CBX4 3'UTR), immunofluorescence of HDAC3 nuclear localization, HDAC3 inhibition, Alizarin red calcification assay Cell Communication and Signaling Low 34980138
2023 In CTL differentiation, CBX4 regulates effector vs. memory fate primarily through its SIM domains (SUMO E3 ligase-related) and partially through its chromodomain; T cell-specific Cbx4 deficiency produces a transcriptional memory signature and expands the memory CTL population. T cell-specific Cbx4 KO mice, CBX4 domain mutant overexpression (SIM and chromodomain mutants), flow cytometry, viral infection model, transcriptional profiling Journal of Immunology Medium 37486206
2025 CBX4 acts as an epigenetic silencer of endogenous retroelements (including RLTR4-Mm-int) through H3K9me3- and H3K27me3-marked chromatin; CBX4 loss derepresses retrotransposons, activating cytosolic RNA-sensing pathways and the type I interferon response, leading to an inflamed tumor microenvironment and enhanced anti-tumor immunity. In vivo CRISPR/Cas9 screens in mouse tumor models, single-cell RNA-seq, spatial transcriptomics, ChIP for H3K9me3/H3K27me3 at retroelements, CBX4 KO in macrophages and tumor cells, IFN response assays Journal of Clinical Investigation High 41915438
2024 CBX4 interacts with EV71 3D RNA polymerase, mediates its SUMOylation and ubiquitination, extends its protein half-life, and thereby promotes EV71 replication; pharmacological inhibition of SUMOylation suppresses 3D stability and viral replication. Co-immunoprecipitation of CBX4–3D polymerase, protein stability (half-life) assay, SUMOylation assay, ubiquitination assay, SUMOylation inhibitor (2-D08) treatment, viral replication assay Frontiers in Microbiology Medium 41859455
2024 Tannic acid promotes interaction between CBX4 and the E3 ubiquitin ligase CUL4A, leading to CBX4 degradation via the ubiquitin-proteasome system; this reduces H3K27me3 enrichment at HIV-1 LTR regions and reactivates latent HIV-1 transcription. Co-immunoprecipitation of CBX4–CUL4A, ubiquitin-proteasome inhibition, ChIP for H3K27me3 at HIV-1 LTR, HIV-1 latency reactivation assay Journal of Virology Medium 39692477
2026 CBX4 suppresses Runx1 expression by recruiting HDAC to the runx1 promoter, reducing H3K27 acetylation at this locus; this regulates monocyte/macrophage lineage fate during zebrafish hematopoiesis and promotes AML-M5-like disease in aging cbx4-overexpressing zebrafish. cbx4 overexpression transgenic and deletion mutant zebrafish, ChIP for HDAC and H3K27ac at runx1 promoter, dual-luciferase reporter assay (HDAC at CERS6/runx1 promoters), flow cytometry of hematopoietic lineages Communications Biology Medium 42225948
2025 CBX4 directly interacts with HIF-1α in macrophages and promotes its sumoylation, increasing HIF-1α transcriptional activity; macrophage-specific CBX4 knockdown alleviates atherosclerosis in HFD-fed ApoE−/− mice, whereas overexpression exacerbates it. Co-immunoprecipitation of CBX4–HIF-1α, sumoylation assay, macrophage-specific CBX4 KD and OE in ApoE−/− mouse model, atherosclerotic lesion quantification Cardiovascular Drugs and Therapy Medium 40478492
2025 CBX4 was identified as a novel interactor of the SS18::SSX fusion oncoprotein in synovial sarcoma cells by mass spectrometry immunoprecipitation using an anti-SS18::SSX antibody. Immunoprecipitation–mass spectrometry in six synovial sarcoma cell lines, immunohistochemistry Laboratory Investigation Low 40992545
2019 GRM4 physically interacts with CBX4 and restricts its nuclear localization, thereby reducing HIF-1α transcriptional activity and inhibiting osteosarcoma cell proliferation, migration and invasion. Co-immunoprecipitation of GRM4–CBX4, subcellular fractionation/immunofluorescence for CBX4 nuclear localization, GRM4 overexpression with HIF-1α luciferase reporter and cell functional assays Bioscience Biotechnology and Biochemistry Low 31581881
2023 In human OA chondrocytes, the CBX4 chromodomain is required for senomorphic regulation of p16INK4A, DPP4, and proliferation, while the SIM domains (not the chromodomain) are required for suppression of SASP secretion; the C-box is largely dispensable for senomorphic function. Lentiviral transduction of CBX4 domain point mutants and deletion mutants in primary OA chondrocytes, flow cytometry (SA-β-gal, p16, DPP4, EdU), multiplex ELISA for SASP, PCR array Arthritis Research & Therapy Medium 37828576

Source papers

Stage 0 corpus · 75 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Cbx4 governs HIF-1α to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer cell 205 24434214
2020 Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma. Nature communications 126 32111827
2012 CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage. Nucleic acids research 122 22402492
2011 Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4. Cell stem cell 120 21885019
2019 Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis. Cell reports 108 30917318
2007 Polycomb protein Cbx4 promotes SUMO modification of de novo DNA methyltransferase Dnmt3a. The Biochemical journal 86 17439403
2016 CBX4 Suppresses Metastasis via Recruitment of HDAC3 to the Runx2 Promoter in Colorectal Carcinoma. Cancer research 83 27864346
2010 A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity. PloS one 65 20098713
2017 CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling. The international journal of biochemistry & cell biology 60 29229426
2013 Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development (Cambridge, England) 60 23362346
2015 Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. The Journal of cell biology 54 26711500
2019 CBX4 promotes the proliferation and metastasis via regulating BMI-1 in lung cancer. Journal of cellular and molecular medicine 50 31724308
2020 LncRNA FOXP4-AS1 Is Involved in Cervical Cancer Progression via Regulating miR-136-5p/CBX4 Axis. OncoTargets and therapy 49 32256085
2020 CBX4 transcriptionally suppresses KLF6 via interaction with HDAC1 to exert oncogenic activities in clear cell renal cell carcinoma. EBioMedicine 46 32113161
2018 miR-129-5p suppresses breast cancer proliferation by targeting CBX4. Neoplasma 45 29940764
2017 DNA end resection requires constitutive sumoylation of CtIP by CBX4. Nature communications 43 28740167
2018 Cbx4 Sumoylates Prdm16 to Regulate Adipose Tissue Thermogenesis. Cell reports 34 29539416
2020 SUMO E3 ligase CBX4 regulates hTERT-mediated transcription of CDH1 and promotes breast cancer cell migration and invasion. The Biochemical journal 33 32926159
2019 MicroRNA-497-5p Induces Cell Cycle Arrest Of Cervical Cancer Cells In S Phase By Targeting CBX4. OncoTargets and therapy 30 31849480
2021 Inhibiting CBX4 efficiently protects hepatocellular carcinoma cells against sorafenib resistance. British journal of cancer 29 33473171
2020 Circular RNA hsa_circ_0008039 promotes proliferation, migration and invasion of breast cancer cells through upregulating CBX4 via sponging miR-515-5p. European review for medical and pharmacological sciences 29 32141558
2017 HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 28283560
2015 MicroRNA-195 functions as a tumor suppressor by inhibiting CBX4 in hepatocellular carcinoma. Oncology reports 28 25607636
2024 CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 27 39154499
2022 CBX4 Regulates Long-Form Thymic Stromal Lymphopoietin-mediated Airway Inflammation through SUMOylation in House Dust Mite-induced Asthma. American journal of respiratory cell and molecular biology 23 35358396
2023 CBX4 deletion promotes tumorigenesis under KrasG12D background by inducing genomic instability. Signal transduction and targeted therapy 22 37696812
2024 CBX4 suppresses CD8+ T cell antitumor immunity by reprogramming glycolytic metabolism. Theranostics 20 38994031
2022 Chromobox 4 (CBX4) promotes tumor progression and stemness via activating CDC20 in gastric cancer. Journal of gastrointestinal oncology 19 35837165
2022 Long Noncoding RNA SNHG5 Induces the NF-κB Pathway by Regulating miR-181c-5p/CBX4 Axis to Promote the Progression of Non-Small Cell Lung Cancer. Archivos de bronconeumologia 18 35963709
2019 Single Nucleotide Polymorphisms of CBX4 and CBX7 Decrease the Risk of Hepatocellular Carcinoma. BioMed research international 17 31211140
2023 Cbx4 governs HIF-1α to involve in Th9 cell differentiation promoting asthma by its SUMO E3 ligase activity. Biochimica et biophysica acta. Molecular cell research 15 37348765
2019 GRM4 inhibits the proliferation, migration, and invasion of human osteosarcoma cells through interaction with CBX4. Bioscience, biotechnology, and biochemistry 14 31581881
2022 CBX4-dependent regulation of HDAC3 nuclear translocation reduces Bmp2-induced osteoblastic differentiation and calcification in adamantinomatous craniopharyngioma. Cell communication and signaling : CCS 13 34980138
2021 Long Non-Coding RNA (lncRNA) RAMS11 Promotes Metastatis and Cell Growth of Prostate Cancer by CBX4 Complex Binding to Top2α. Cancer management and research 13 33564266
2022 MicroRNA-6838-5p suppresses the self-renewal and metastasis of human liver cancer stem cells through downregulating CBX4 expression and inactivating ERK signaling. Biological chemistry 12 36215729
2022 MiR-507 inhibits the progression of gastric carcinoma via targeting CBX4-mediated activation of Wnt/β-catenin and HIF-1α pathways. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 10 35819589
2024 Cbx4 SUMOylates BRD4 to regulate the expression of inflammatory cytokines in post-traumatic osteoarthritis. Experimental & molecular medicine 9 39349832
2023 CBX4 promotes antitumor immunity by suppressing Pdcd1 expression in T cells. Molecular oncology 9 37691307
2022 CBX4 Regulates Replicative Senescence of WI-38 Fibroblasts. Oxidative medicine and cellular longevity 9 35251476
2021 miR-515-5p inhibits the proliferation, migration and invasion of human breast cancer cells by targeting CBX4. Experimental and therapeutic medicine 9 34630682
2025 A specific form of cPRC1 containing CBX4 is co-opted to mediate oncogenic gene repression in diffuse midline glioma. Molecular cell 8 40403727
2022 Associations of genetic variation in E3 SUMO-protein ligase CBX4 with noise-induced hearing loss. Human molecular genetics 7 35038734
2025 CBX4 regulation of senescence and associated diseases: Molecular pathways and mechanisms. Pharmacological research 6 40120729
2024 METTL3 Promotes Osteosarcoma Metastasis via an m6A-dependent Epigenetic Activity of CBX4. Frontiers in bioscience (Landmark edition) 6 38538251
2024 CBX4 plays a bidirectional role in transcriptional regulation and lung adenocarcinoma progression. Cell death & disease 6 38816356
2013 Contribution of CBX4 to cumulus oophorus cell phenotype in mice and attendant effects in cumulus cell cloned embryos. Physiological genomics 6 24280258
2023 Cancer-associated fibroblasts promote cancer stemness by inducing expression of the chromatin-modifying protein CBX4 in squamous cell carcinoma. Carcinogenesis 5 37463322
2021 SALL1 Modulates CBX4 Stability, Nuclear Bodies, and Regulation of Target Genes. Frontiers in cell and developmental biology 5 34621739
2025 CBX4 acetoacetylation as an inhibitory mechanism of HIF-1α activity. Cell chemical biology 4 41045931
2015 Cbx4: A new guardian of p63's domain of epidermal control. The Journal of cell biology 4 26711501
2024 Predictive Values of Homeobox Gene A-Antisense Transcript 3 (HOXA-AS3), Cystatin 6 (CST6), and Chromobox Homolog 4 (CBX4) Expressions in Cancer Tissues for Recurrence of Early Colon Cancer After Surgery. International journal of general medicine 3 38196563
2024 Ziyuglycoside II, a triterpene glycoside compound in Sanguisorbae officinalis l. extract, suppresses metastasis in osteosarcoma via CBX4-mediated Wnt/β-catenin signal pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 3 38924929
2022 The Role of LINC01564, RAMS11, CBX4 and TOP2A in Hepatocellular Carcinoma. Biomedicines 3 36672564
2021 The predictive potential of genetic single nucleotide polymorphisms in CBX4 for hepatocellular carcinoma survival. Frontiers in bioscience (Landmark edition) 3 34856763
2025 Macrophage CBX4 Potentiates Atherosclerosis by its SUMO E3 Ligase Activity. Cardiovascular drugs and therapy 2 40478492
2024 Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection. Cancers 2 38893273
2024 CBX4/miR-190 regulatory loop inhibits lung cancer metastasis. Thoracic cancer 2 39098997
2023 Cutting Edge: Polycomb Repressive Complex 1 Subunit Cbx4 Positively Regulates Effector Responses in CD8 T Cells. Journal of immunology (Baltimore, Md. : 1950) 2 37486206
2023 Synergistic roles of CBX4 chromo and SIM domains in regulating senescence of primary human osteoarthritic chondrocytes. Arthritis research & therapy 2 37828576
2022 CBX4 contributes to radioresistance by regulating autophagic activity in esophageal squamous cell carcinoma. Annals of translational medicine 2 36267739
2025 Integrating Single-Cell and Bulk RNA Sequencing Reveals the Malignant Phenotype of CBX4 in Prostate Cancer. Journal of Cancer 1 40861818
2024 ABRACL upregulated by transcription factor CBX4 promotes proliferation and migration and inhibits the apoptosis of gastric cancer cells. Histology and histopathology 1 39376051
2024 Tannic acid reactivates HIV-1 latency by mediating CBX4 degradation. Journal of virology 1 39692477
2026 CBX4 facilitates EV71 replication by SUMOylation and stabilizing 3D polymerase. Frontiers in microbiology 0 41859455
2026 Integrative Transcriptomics and Machine Learning Reveal the Association of CBX4 with Inflammation in Ulcerative Colitis as a Potential Epigenetic Regulator. Biomedicines 0 41898331
2026 In vivo CRISPR screens identify CBX4 as an epigenetic regulator for cancer immunotherapy. The Journal of clinical investigation 0 41915438
2026 Correction: CBX4 facilitates EV71 replication by SUMOylation and stabilizing 3D polymerase. Frontiers in microbiology 0 42052387
2026 CBX4 enhances acute monocytic leukemia development via HDAC-mediated suppression of Runx1. Communications biology 0 42225948
2025 The Roles of CBX4 in Gastrointestinal Cancer. Discovery medicine 0 40415358
2025 Not all CBXs are created equal: A role for the disordered central region of CBX4 in pediatric glioma. Molecular cell 0 40480193
2025 Investigation of CBX4 Polymorphisms and Their Association with Clinicopathological Features in Asian Patients with Oral Squamous Cell Carcinoma. Journal of Cancer 0 40740235
2025 Chromobox 4 (CBX4) Is a Novel Interactor of SS18::SSX in Synovial Sarcoma. Laboratory investigation; a journal of technical methods and pathology 0 40992545
2025 Role and mechanism of the CBX4-HDAC5-CERS6 axis in disrupting sphingomyelin metabolism in acute myeloid leukemia. American journal of cancer research 0 41395279
2025 CBX4 Drives Gastric Cancer Progression by Activating β-Catenin Signaling. Oncology research 0 41502529
2024 Formononetin suppresses the malignant progression of papillary thyroid carcinoma depending on downregulation of CBX4. Experimental and therapeutic medicine 0 39478737

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