CXXC4

Summary

CXXC4 (CXXC finger protein 4, HGNC:24593) is a protein-coding gene on chromosome 4q24, encoding CXXC-type zinc finger protein 4 (Q9H2H0). Acts as a negative regulator of the Wnt signaling pathway via its interaction with DVL1.

This gene encodes a CXXC-type zinc finger domain-containing protein that functions as an antagonist of the canonical wingless/integrated signaling pathway. The encoded protein negatively regulates wingless/integrated signaling through interaction with the post synaptic density protein/ Drosophila disc large tumor suppressor/ zonula occludens-1 protein domain of Dishevelled, a scaffolding protein required for the stabilization of the transcriptional co-activator beta-catenin. In addition, the CXXC domain of this protein has been shown to bind unmethylated CpG dinucleotides, localize to promoters and CpG islands, and interact with the catalytic domain of methylcytosine dioxygenase ten-eleven-translocation 2, an iron and alpha-ketoglutarate-dependent dioxygenase that modifies the methylation status of DNA. In humans, a mutation in this gene has been associated with development of malignant renal cell carcinoma. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 80319 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 27 total
• Druggable target: yes
• MANE Select transcript: NM_025212

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24593
Approved symbol	CXXC4
Name	CXXC finger protein 4
Location	4q24
Locus type	gene with protein product
Status	Approved
Aliases	IDAX
Ensembl gene	ENSG00000168772
Ensembl biotype	protein_coding
OMIM	611645
Entrez	80319

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000394767, ENST00000466963, ENST00000515509, ENST00000698535

RefSeq mRNA: 1 — MANE Select: NM_025212 NM_025212

CCDS: CCDS3665

Canonical transcript exons

ENST00000394767 — 3 exons

Exon	Start	End
ENSE00001408860	104494701	104494894
ENSE00001519503	104468308	104472366
ENSE00001519504	104490744	104492059

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 85.74.

FANTOM5 (CAGE): breadth broad, TPM avg 5.2752 / max 364.8029, expressed in 528 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53455	4.9779	519
53454	0.1714	107
53456	0.1260	66

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	85.74	gold quality
secondary oocyte	CL:0000655	83.70	gold quality
ventricular zone	UBERON:0003053	82.33	gold quality
bronchial epithelial cell	CL:0002328	81.99	gold quality
ganglionic eminence	UBERON:0004023	81.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.77	gold quality
epithelium of bronchus	UBERON:0002031	79.96	gold quality
Brodmann (1909) area 46	UBERON:0006483	79.43	silver quality
islet of Langerhans	UBERON:0000006	79.41	gold quality
bronchus	UBERON:0002185	79.12	gold quality
right uterine tube	UBERON:0001302	78.52	gold quality
middle temporal gyrus	UBERON:0002771	78.31	silver quality
parotid gland	UBERON:0001831	77.95	silver quality
cortical plate	UBERON:0005343	77.29	gold quality
embryo	UBERON:0000922	76.52	gold quality
prefrontal cortex	UBERON:0000451	75.44	gold quality
entorhinal cortex	UBERON:0002728	75.10	gold quality
hypothalamus	UBERON:0001898	74.85	gold quality
superior frontal gyrus	UBERON:0002661	74.78	gold quality
pancreas	UBERON:0001264	74.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	74.42	gold quality
cerebellar vermis	UBERON:0004720	74.39	gold quality
pigmented layer of retina	UBERON:0001782	74.31	gold quality
body of pancreas	UBERON:0001150	74.29	gold quality
primary visual cortex	UBERON:0002436	74.15	gold quality
pituitary gland	UBERON:0000007	73.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	73.65	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.42	gold quality
neocortex	UBERON:0001950	73.36	gold quality
frontal cortex	UBERON:0001870	73.22	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	14.68
E-ANND-3	yes	7.74
E-GEOD-83139	no	3.71

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

291 targeting CXXC4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616

Literature-anchored findings (GeneRIF, showing 11)

• Decreased CXXC4 was associated with kidney cancer metastasis, poor survival, beta-catenin translocation, cell proliferation, reduced apoptosis in response to cancer drugs, and upregulation of genes involed in proliferation, invasion, and cell survival. (PMID:18931698)
• IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation (PMID:23563267)
• CXXC4 is a novel potential tumor suppressor directly regulated by EZH2, and its expression is a significant prognosis factor for patients with early stages of gastric cancer. (PMID:23949225)
• EZH2 can activate MAPK signaling by inhibiting CXXC4 expression. (PMID:25064842)
• Age of patients and levels of CXXC4 mRNA, hemoglobin, and marrow blast associated with survival of Myelodysplastic syndrome patients. (PMID:25085016)
• The findings indicate that BMI1-mediated IDAX epigenetic suppression is crucial for enhancement of colon carcinogenesis. (PMID:29337063)
• The results presented here suggest that miR-629-5p functions as a tumor promoter by improving proliferation and migration and repressing apoptosis and 5-FU sensitivity in colorectal cancer progression by directly down-regulating CXXC4. (PMID:30042169)
• CXXC finger protein 4 inhibits the CDK18-ERK1/2 axis to suppress the immune escape of gastric cancer cells with involvement of ELK1/MIR100HG pathway. (PMID:32715641)
• LUCAT1 Epigenetically Downregulates the Tumor Suppressor Genes CXXC4 and SFRP2 in Gastric Cancer. (PMID:33107235)
• Malignant Transformation Involving CXXC4 Mutations Identified in a Leukemic Progression Model of Severe Congenital Neutropenia. (PMID:33205068)
• SPZ1 promotes glioma aggravation via targeting CXXC4. (PMID:34076982)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cxxc4	ENSDARG00000077817
mus_musculus	Cxxc4	ENSMUSG00000044365
rattus_norvegicus		ENSRNOG00000084996

Paralogs (1): CXXC5 (ENSG00000171604)

Protein

Protein identifiers

CXXC-type zinc finger protein 4 — Q9H2H0 (reviewed: Q9H2H0)

Alternative names: Inhibition of the Dvl and axin complex protein

All UniProt accessions (2): A0A8V8TLX0, J9JIF5

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a negative regulator of the Wnt signaling pathway via its interaction with DVL1. Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG.

Subunit / interactions. Interacts with the PDZ domain of DVL1.

Subcellular location. Cytoplasm.

Domain organisation. The CXXC zinc finger mediates binding to CpG-DNA.

RefSeq proteins (1): NP_079488* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002857	Znf_CXXC	Domain
IPR040388	CXXC4/CXXC5	Family

Pfam: PF02008

UniProt features (17 total): binding site 8, helix 4, region of interest 2, chain 1, zinc finger region 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5VC9	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2H0-F1	64.52	0.21

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 167; 172; 139; 142; 145; 151; 154; 157

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5368598	Negative regulation of TCF-dependent signaling by DVL-interacting proteins

MSigDB gene sets: 195 (showing top): GOBP_AXIS_SPECIFICATION, chr4q24, GOBP_EMBRYONIC_AXIS_SPECIFICATION, NKX25_02, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, CAGCTG_AP4_Q5, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_EMBRYONIC_PATTERN_SPECIFICATION, AACTTT_UNKNOWN, IK2_01, VDR_Q3, GOBP_EMBRYO_DEVELOPMENT, OCT1_B, GOBP_DORSAL_VENTRAL_AXIS_SPECIFICATION, GOBP_NEGATIVE_REGULATION_OF_WNT_SIGNALING_PATHWAY

GO Biological Process (3): zygotic specification of dorsal/ventral axis (GO:0007352), Wnt signaling pathway (GO:0016055), negative regulation of Wnt signaling pathway (GO:0030178)

GO Molecular Function (5): zinc ion binding (GO:0008270), methyl-CpG binding (GO:0008327), PDZ domain binding (GO:0030165), DNA binding (GO:0003677), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
embryonic axis specification	1
dorsal/ventral axis specification	1
cell surface receptor signaling pathway	1
negative regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
transition metal ion binding	1
nucleotide binding	1
sequence-specific DNA binding	1
protein domain specific binding	1
nucleic acid binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

432 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CXXC4	TET2	Q6N021	923
CXXC4	DVL1	O14640	829
CXXC4	AXIN1	O15169	620
CXXC4	OGT	O15294	574
CXXC4	TCF7L2	Q9NQB0	567
CXXC4	WT1	P19544	558
CXXC4	WNT3A	P56704	545
CXXC4	TET3	O43151	531
CXXC4	SIN3A	Q96ST3	518
CXXC4	CTNNB1	P35222	513
CXXC4	TDG	Q13569	494
CXXC4	DPPA3	Q6W0C5	485
CXXC4	DACT1	Q9NYF0	475
CXXC4	FZD9	O00144	475
CXXC4	FOXL2	P58012	473

IntAct

4 interactions, top by confidence:

A	B	Type	Score
CXXC4	TIA1	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A1B0GUA6, A0A2K1JJ00, A0JMD2, A2AWL7, A2VCZ5, A4IGV6, A6NDR6, A8E653, A9ZPC9, B3DHS1, B8JKP6, B9EJV3, D3Z3C6, P06434, P08651, P09414, P0DH66, P0DH68, P17923, P21999, P97368, Q02780, Q03172, Q0VFP6, Q12857, Q1KN21, Q1LY84, Q1X6Y6, Q5SPL2, Q5SWW4, Q62417, Q6DFB0, Q6JPI3, Q6NWJ0, Q6NXI8, Q6P1U0, Q6P9N1, Q6PKN7, Q6ZPK7, Q8BIA3

Diamond homologs: A0A1L8GSA2, A0JP82, K9JHZ4, M9NEY8, O43151, Q0VFP6, Q32LB3, Q4JK59, Q5R7N4, Q5XIQ3, Q6N021, Q6NXI8, Q7LFL8, Q800L6, Q8BG87, Q8NFU7, Q91WA4, Q9EQC9, Q9H2H0, Q3URK3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

27 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

617 predictions. Top by Δscore:

Variant	Effect	Δscore
4:104472314:C:CT	donor_gain	1.0000
4:104472315:T:TT	donor_gain	1.0000
4:104494500:ACTT:A	donor_loss	0.9900
4:104494501:CTTA:C	donor_loss	0.9900
4:104494502:TTACC:T	donor_loss	0.9900
4:104494503:TACCA:T	donor_loss	0.9900
4:104494504:ACCAG:A	donor_loss	0.9900
4:104494505:C:T	donor_loss	0.9900
4:104494505:CCAGT:C	donor_gain	0.9900
4:104472314:CTA:C	donor_gain	0.9800
4:104494499:CACT:C	donor_loss	0.9700
4:104494504:A:AC	donor_gain	0.9700
4:104494505:C:CC	donor_gain	0.9700
4:104494505:CCA:C	donor_gain	0.9600
4:104491980:ATT:A	donor_gain	0.9500
4:104494848:T:A	donor_gain	0.9500
4:104487129:T:TA	donor_gain	0.9400
4:104491982:T:TA	donor_gain	0.9400
4:104472317:C:CC	donor_gain	0.9300
4:104472365:CT:C	acceptor_gain	0.9300
4:104476961:A:AC	donor_gain	0.9300
4:104476962:C:CC	donor_gain	0.9300
4:104487136:T:TA	donor_gain	0.9300
4:104492418:C:CT	donor_gain	0.9100
4:104492419:T:TT	donor_gain	0.9100
4:104472313:A:AC	donor_gain	0.9000
4:104472367:C:CC	acceptor_gain	0.8900
4:104492057:CAA:C	acceptor_gain	0.8700
4:104492060:C:CC	acceptor_gain	0.8700
4:104492059:ACT:A	acceptor_gain	0.8600

AlphaMissense

2373 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002205 (4:104478637 A>G), RS1000007070 (4:104488037 G>A), RS1000055340 (4:104478303 C>A), RS1000117014 (4:104496564 C>T), RS1000238464 (4:104496031 C>T), RS1000285912 (4:104485184 T>A), RS1000370288 (4:104474746 T>A,C), RS1000486470 (4:104474477 G>C), RS1000647953 (4:104494970 A>C,T), RS1000843775 (4:104494266 C>T), RS1000888015 (4:104486814 T>C,G), RS1000971029 (4:104473065 T>G), RS1000977133 (4:104486812 C>T), RS1001006495 (4:104480226 G>T), RS1001008492 (4:104486466 C>T)

Disease associations

OMIM: gene MIM:611645 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002937_10	Molybdenum levels	4.000000e-06
GCST003993_10	Menarche (age at onset)	3.000000e-08
GCST005790_93	Rosacea symptom severity	6.000000e-06
GCST007201_406	Schizophrenia	9.000000e-07
GCST007201_467	Schizophrenia	8.000000e-07
GCST007576_318	Chronotype	1.000000e-08
GCST009391_1350	Metabolite levels	2.000000e-06
GCST012489_31	Heel bone mineral density x serum urate levels interaction	4.000000e-08
GCST90011900_88	Serum alkaline phosphatase levels	4.000000e-17

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0009180	rosacea severity measurement
EFO:0008328	chronotype measurement
EFO:0010363	lysophosphatidylcholine 20:4 measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169197 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4413407	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4413407	CXXC4	3	3.00	1	Platinum compounds

ChEMBL bioactivities

6 potent at pChembl≥5 of 9 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.92	IC50	1200	nM	CHEMBL5189434
5.66	IC50	2200	nM	CHEMBL5181110
5.62	IC50	2400	nM	CHEMBL5177921
5.40	IC50	4000	nM	CHEMBL5194845
5.08	IC50	8300	nM	CHEMBL5178563
5.05	IC50	8900	nM	CHEMBL5201158

PubChem BioAssay actives

6 with measured affinity, of 9 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-(4-ethoxyphenyl)-1-prop-2-enoylpiperidine-4-carboxylic acid	1871102: Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	ic50	1.2000	uM
1-[4-(3-ethoxyphenyl)-4-(2H-tetrazol-5-yl)piperidin-1-yl]prop-2-en-1-one	1871102: Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	ic50	2.2000	uM
1-[4-phenyl-4-(2H-tetrazol-5-yl)piperidin-1-yl]prop-2-en-1-one	1871102: Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	ic50	2.4000	uM
4-phenyl-1-prop-2-enoylpiperidine-4-carboxylic acid	1871102: Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	ic50	4.0000	uM
1-[4-(4-methoxyphenyl)-4-(2H-tetrazol-5-yl)piperidin-1-yl]prop-2-en-1-one	1871102: Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	ic50	8.3000	uM
1-[4-(4-ethoxyphenyl)-4-(2H-tetrazol-5-yl)piperidin-1-yl]prop-2-en-1-one	1871102: Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	ic50	8.9000	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, increases expression	3
entinostat	decreases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Silicon Dioxide	decreases expression	2
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	increases expression	1
bisphenol A	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	decreases expression	1
Sunitinib	decreases expression	1
Glyphosate	decreases expression	1
Camptothecin	increases expression	1
Dimethyl Sulfoxide	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5126413	Binding	Inhibition of GST-tagged human IDAX (130 to 181 residues) expressed in Escherichia coli BL21 cells incubated for 30 mins by fluorescence polarization assay	Small-Molecule Inhibitors of the MLL1 CXXC Domain, an Epigenetic Reader of DNA Methylation. — ACS Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0BF	Ubigene HeLa CXXC4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.