ING4

Summary

ING4 (inhibitor of growth family member 4, HGNC:19423) is a protein-coding gene on chromosome 12p13.31, encoding Inhibitor of growth protein 4 (Q9UNL4). Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at ‘Lys-14’ (H3K14ac), and have reduced activity toward histone H4.

This gene encodes a tumor suppressor protein that contains a PHD-finger, which is a common motif in proteins involved in chromatin remodeling. This protein can bind TP53 and EP300/p300, a component of the histone acetyl transferase complex, suggesting its involvement in the TP53-dependent regulatory pathway. Multiple alternatively spliced transcript variants have been observed that encode distinct proteins.

Source: NCBI Gene 51147 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 32 total
• Transcription factor: yes — 15 downstream targets (CollecTRI)
• MANE Select transcript: NM_016162

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19423
Approved symbol	ING4
Name	inhibitor of growth family member 4
Location	12p13.31
Locus type	gene with protein product
Status	Approved
Aliases	p29ING4, my036
Ensembl gene	ENSG00000111653
Ensembl biotype	protein_coding
OMIM	608524
Entrez	51147

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000341550, ENST00000396807, ENST00000412586, ENST00000423703, ENST00000437149, ENST00000444704, ENST00000446105, ENST00000467678, ENST00000469749, ENST00000472002, ENST00000479301, ENST00000482489, ENST00000484795, ENST00000486287, ENST00000488381, ENST00000493267, ENST00000493873, ENST00000619641, ENST00000906757, ENST00000906758, ENST00000906759, ENST00000906760, ENST00000906761, ENST00000906762, ENST00000906763, ENST00000906764

RefSeq mRNA: 6 — MANE Select: NM_016162 NM_001127582, NM_001127583, NM_001127584, NM_001127585, NM_001127586, NM_016162

CCDS: CCDS44812, CCDS44813, CCDS44814, CCDS44815, CCDS44816, CCDS8555

Canonical transcript exons

ENST00000341550 — 8 exons

Exon	Start	End
ENSE00001951179	6650301	6651234
ENSE00002199712	6663065	6663119
ENSE00003475073	6652936	6653050
ENSE00003477299	6651324	6651385
ENSE00003478068	6656727	6656798
ENSE00003525667	6652662	6652767
ENSE00003651160	6652271	6652418
ENSE00003681729	6653230	6653396

Expression profiles

Bgee: expression breadth ubiquitous, 268 present calls, max score 97.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.3105 / max 387.1359, expressed in 1784 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129154	14.8230	1779
129155	0.4875	258

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	97.63	gold quality
ganglionic eminence	UBERON:0004023	97.12	gold quality
monocyte	CL:0000576	96.45	gold quality
mononuclear cell	CL:0000842	95.90	gold quality
ventricular zone	UBERON:0003053	95.63	gold quality
leukocyte	CL:0000738	95.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.47	gold quality
cerebellar hemisphere	UBERON:0002245	95.40	gold quality
cerebellar cortex	UBERON:0002129	95.32	gold quality
right uterine tube	UBERON:0001302	94.80	gold quality
granulocyte	CL:0000094	94.69	gold quality
right lobe of thyroid gland	UBERON:0001119	94.60	gold quality
left lobe of thyroid gland	UBERON:0001120	94.60	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.17	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.10	gold quality
right frontal lobe	UBERON:0002810	94.04	gold quality
endocervix	UBERON:0000458	93.95	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.90	gold quality
lower esophagus	UBERON:0013473	93.89	gold quality
body of uterus	UBERON:0009853	93.78	gold quality
cerebellum	UBERON:0002037	93.74	gold quality
thyroid gland	UBERON:0002046	93.73	gold quality
left ovary	UBERON:0002119	93.71	gold quality
descending thoracic aorta	UBERON:0002345	93.67	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.62	gold quality
right ovary	UBERON:0002118	93.61	gold quality
popliteal artery	UBERON:0002250	93.59	gold quality
tibial artery	UBERON:0007610	93.59	gold quality
stromal cell of endometrium	CL:0002255	93.53	gold quality
rectum	UBERON:0001052	93.53	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

15 targets.

Target	Regulation
ANGPT1	Repression
ARL6IP5	Activation
BAX	Activation
BCL2	Repression
CASP3	Activation
CCND1	Repression
CDKN1A	Activation
CDKN1B	Activation
CXCL8	Repression
NGF	Repression
NTRK1	Repression
PTGS2	Repression
SKP2	Repression
SPP1	Repression
TP53	Activation

Upstream regulators (CollecTRI, top): FOXC1, IRF6, MYC, NFKB, RELA, RUNX3

Literature-anchored findings (GeneRIF, showing 40)

• p29ING4 and p28ING5 may be significant modulators of p53 function. (PMID:12750254)
• In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours (PMID:15029197)
• ING4 induces G2/M cell cycle arrest and enhances the chemosensitivity to DNA-damage agents in HepG2 cells (PMID:15251430)
• detected deletion of the ING4 locus in 10-20% of human breast cancer cell lines and primary breast tumors, supporting the possibility that ING4 might be a tumor suppressor gene (PMID:15528276)
• NLS domain of ING4 is essential for the binding of ING4 to p53 and the function of ING4 associated with p53 (PMID:15882981)
• ING4 represses activation of the hypoxia inducible factor. (PMID:15897452)
• Frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer. (PMID:15935570)
• mediates the ability of HIF to activate transcription of its downstream target genes [review] (PMID:16096374)
• Splice variants of ING4 are associated with cell growth and motility of cancer cells (PMID:16973615)
• data suggest that alternative splicing could modulate the activity of ING4 tumor suppressor protein (PMID:17325660)
• provide evidence for the role of ING4 in mediating the effect of low K intake on renal outer medullary K channel activity by stimulation of p38 and ERK mitogen-activated protein kinase (PMID:17517644)
• ING4 exerts an inhibitory effect on the production of proangiogenic molecules and consequently on MM-induced angiogenesis (PMID:17848618)
• may play an inhibitory role in lung adenocarcinoma by up-regulation or down-regulation of cell proliferation-regulating proteins such as p27, cyclinD1, SKP2, and Cox2 by means of inactivation of Wnt-1/beta-catenin signaling (PMID:18399550)
• Data suggest that the two wobble-splicing events at the exon 4-5 boundary influence subnuclear localization and degradation of ING4. (PMID:18775696)
• ING4 may specifically regulate the activity of NF-kappaB molecules that are bound to target gene promoters. (PMID:18779315)
• HCC risk associated with heavy alcohol intake and current smoking differed by this polymorphism among CLD patients. IL-1B -31T/C polymorphism may modify HCC risk in relation to alcohol intake or smoking (PMID:18789575)
• Findings suggest that exogenous ING4 can enhance A549 apoptosis via regulating the expression of Bcl-2 family proteins and the activation of mitochondrial apoptotic pathway. (PMID:19034511)
• Report down-regulation of the inhibitor of growth family member 4 (ING4) in different forms of pulmonary fibrosis. (PMID:19250543)
• ING4 has a potential role in growth suppression and apoptosis enhancement of melanoma through the activation of the mitochondrial-induced apoptotic pathway and the hindrance of the cell cycle. The deregulation of ING4 might be involved in melanomagenesis. (PMID:19430401)
• ING4 has a potential role on the growth suppression and apoptosis enhancement in gliomas U87MG via the activation of mitochondrial-induced apoptotic pathway and the hindrance of the cell cycle progression. (PMID:19571607)
• our data suggest an essential role for ING-4 in human astrocytoma development and progression possibly through regulation of the NF-kappaB-dependent expression of genes involved in tumor invasion (PMID:19775294)
• results show that ING4 is a bivalent reader of the chromatin H3K4me3 modification and suggest a mechanism for enhanced targeting of the HBO1 complex to specific chromatin sites (PMID:20053357)
• over-expression of miR-650 in gastric cancer may promote proliferation and growth of cancer cells, at least partially through directly targeting ING4. (PMID:20381459)
• A dominant mutant allele of the ING4 tumor suppressor found in human cancer cells exacerbates MYC-initiated mouse mammary tumorigenesis. (PMID:20501848)
• Mutations in ING4 is associated with cancer. (PMID:20705953)
• Loss of ING4 is associated with breast carcinoma. (PMID:20707719)
• Demonstrated decreased ING4 mRNA and expression in 100% (50/50) lung tumour tissues. Furthermore, ING4 expression was lower in grade III than in grades I-II tumours. Reduced ING4 mRNA correlated with lymph node metastasis. (PMID:20716169)
• ING4 is induced by BRMS1 and that it inhibits melanoma angiogenesis by suppressing NF-kappaB activity and IL-6 expression. (PMID:21056991)
• EBNA3C negatively regulate p53-mediated functions by interacting with ING4 and ING5. (PMID:21177815)
• results suggest that the decreases in nuclear ING4 may play important roles in tumorigenesis, progression and tumor differentiation in head and neck squamous cell carcinoma. (PMID:21310648)
• These results sustain the view that ING4 is a tumor suppressor in breast cancer and suggest that ING4 deletion may contribute to the pathogenesis of HER2-positive breast cancer. (PMID:21315418)
• Citrullination of inhibitor of growth 4 (ING4) by peptidylarginine deminase 4 (PAD4) disrupts the interaction between ING4 and p53 (PMID:21454715)
• Downregulated expression of inhibitor of growth 4 is associated with colorectal cancers. (PMID:21626442)
• In this review, the different properties of ING4 are discussed, and its activities are correlated with different aspects of cell physiology. [Review] (PMID:21971889)
• Mechanism of ING4 mediated inhibition of the proliferation and migration of human glioma cell line U251. (PMID:22078444)
• Data suggest that ING4 may be a promising target for the treatment for ovarian cancer. (PMID:22228137)
• crystal structure of the ING4 N-terminal domain (PMID:22334692)
• Inhibitor of growth 4 may represent an important biomarker for assessing the severity of breast cancer (PMID:22436625)
• Data suggested that miR-650 is correlated with the pathogenesis of hepatocellular carcinoma (HCC) and is involved in the HCC tumorigenesis process by inhibiting the expression of ING4. (PMID:22767438)
• Loss of ING4 expression is associated with lymphatic metastasis in colon cancer. (PMID:23055189)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ing4	ENSDARG00000030716
mus_musculus	Ing4	ENSMUSG00000030330
rattus_norvegicus	Ing4	ENSRNOG00000023363
drosophila_melanogaster	CG7379	FBGN0038546
caenorhabditis_elegans		WBGENE00020287

Paralogs (4): ING3 (ENSG00000071243), ING1 (ENSG00000153487), ING5 (ENSG00000168395), ING2 (ENSG00000168556)

Protein

Protein identifiers

Inhibitor of growth protein 4 — Q9UNL4 (reviewed: Q9UNL4)

Alternative names: p29ING4

All UniProt accessions (6): Q9UNL4, A4KYM5, E9PJ14, E9PNE3, H0YEH7, R4GNG1

UniProt curated annotations — full annotation on UniProt →

Function. Component of HBO1 complexes, which specifically mediate acetylation of histone H3 at ‘Lys-14’ (H3K14ac), and have reduced activity toward histone H4. Through chromatin acetylation it may function in DNA replication. May inhibit tumor progression by modulating the transcriptional output of signaling pathways which regulate cell proliferation. Can suppress brain tumor angiogenesis through transcriptional repression of RELA/NFKB3 target genes when complexed with RELA. May also specifically suppress loss of contact inhibition elicited by activated oncogenes such as MYC. Represses hypoxia inducible factor’s (HIF) activity by interacting with HIF prolyl hydroxylase 2 (EGLN1). Can enhance apoptosis induced by serum starvation in mammary epithelial cell line HC11.

Subunit / interactions. Homodimer. Component of the HBO1 complex composed of KAT7/HBO1, MEAF6, ING4 or ING5, and one scaffold subunit: complexes containing BRPF scaffold (BRPF1, BRD1/BRPF2 or BRPF3) direct KAT7/HBO1 specificity towards H3K14ac, while complexes containing JADE scaffold (JADE1, JADE2 and JADE3) mediate acetylation of histone H4. Interacts with H3K4me3 and to a lesser extent with H3K4me2, the interaction augments KAT7/HBO1 acetylation activity on H3 tails. Interacts with EP300, RELA and TP53; these interactions may be indirect. Interacts with EGLN1. Interacts with BCL2A1.

Subcellular location. Nucleus.

Post-translational modifications. Citrullination by PADI4 within the nuclear localization signal disrupts the interaction with p53 and increases susceptibility to degradation.

Domain organisation. The PHD-type zinc finger mediates the binding to H3K4me3. The N-terminal coiled-coil domain mediates homodimerization.

Miscellaneous. May be due to a competing donor splice site. Lacks the nuclear localization signal (NLS), resulting in increased cytoplasmic localization. Lacks the nuclear localization signal (NLS), resulting in increased cytoplasmic localization. Lacks the nuclear localization signal (NLS), resulting in increased cytoplasmic localization.

Similarity. Belongs to the ING family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q9UNL4-1	1, ING4_v1	yes
Q9UNL4-2	2
Q9UNL4-3	3, deltaEx2
Q9UNL4-4	4, ING4_v4
Q9UNL4-5	5
Q9UNL4-6	6, ING4_v2
Q9UNL4-7	7, ING4_v3
Q9UNL4-8	8, deltaEx6A

RefSeq proteins (6): NP_001121054, NP_001121055, NP_001121056, NP_001121057, NP_001121058, NP_057246* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001965	Znf_PHD	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR024610	ING_N_histone-binding	Domain
IPR028651	ING_fam	Family

Pfam: PF12998

UniProt features (45 total): modified residue 10, binding site 8, splice variant 8, helix 7, site 4, strand 2, chain 1, zinc finger region 1, region of interest 1, coiled-coil region 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2VNF	X-RAY DIFFRACTION	1.76
2PNX	X-RAY DIFFRACTION	1.8
4AFL	X-RAY DIFFRACTION	2.27
2K1J	SOLUTION NMR
2M1R	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNL4-F1	77.14	0.39

Functional residue map

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

Catalytic / active sites (4): 198 (histone h3k4me3 binding); 209 (histone h3k4me3 binding); 213 (histone h3k4me3 binding); 221 (histone h3k4me3 binding)

Ligand- & substrate-binding residues (8): 226; 239; 242; 199; 201; 212; 217; 223

Post-translational modifications (10): 112, 127, 129, 133, 146, 148, 156, 166, 114, 127

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 239 (showing top): ATF_B, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, CCAWYNNGAAR_UNKNOWN, GCM_GSPT1, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, GCAAGGA_MIR502, GOBP_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, CREB_Q4, GOBP_POSITIVE_REGULATION_OF_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_PROTEIN_ACETYLATION, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_REGULATION_OF_CELL_CYCLE, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN

GO Biological Process (16): regulation of cell growth (GO:0001558), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), protein acetylation (GO:0006473), apoptotic process (GO:0006915), negative regulation of cell population proliferation (GO:0008285), positive regulation of apoptotic process (GO:0043065), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), negative regulation of DNA-templated transcription (GO:0045892), negative regulation of growth (GO:0045926), regulation of cell cycle (GO:0051726), DNA replication-dependent chromatin disassembly (GO:0140889), regulation of cell cycle G2/M phase transition (GO:1902749), regulation of DNA biosynthetic process (GO:2000278), chromatin organization (GO:0006325), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (9): transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), histone H3K4me3 reader activity (GO:0140002), protein binding (GO:0005515), histone H3K14 acetyltransferase activity (GO:0036408), histone H4K5 acetyltransferase activity (GO:0043995), histone H4K8 acetyltransferase activity (GO:0043996), histone H4K12 acetyltransferase activity (GO:0043997), metal ion binding (GO:0046872)

GO Cellular Component (5): histone acetyltransferase complex (GO:0000123), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), intermediate filament cytoskeleton (GO:0045111)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	3
histone H4 acetyltransferase activity	3
regulation of growth	2
chromatin organization	2
regulation of DNA-templated transcription	2
cellular anatomical structure	2
cell growth	1
regulation of cellular component organization	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
protein acylation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
negative regulation of RNA biosynthetic process	1
growth	1
negative regulation of biological process	1
cell cycle	1
regulation of cellular process	1
cell cycle G2/M phase transition	1
regulation of cell cycle phase transition	1
regulation of macromolecule biosynthetic process	1
regulation of DNA metabolic process	1
DNA biosynthetic process	1
cellular component organization	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
transition metal ion binding	1
histone H3 reader activity	1
binding	1

Protein interactions and networks

STRING

1270 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ING4	KAT7	O95251	998
ING4	MEAF6	Q9HAF1	993
ING4	JADE1	Q6IE81	985
ING4	ASXL2	Q76L83	864
ING4	TP53	P04637	864
ING4	RELA	Q04206	856
ING4	BRPF1	P55201	848
ING4	EP300	Q09472	837
ING4	KAT6B	Q8WYB5	817
ING4	PPFIA1	Q13136	787
ING4	EGLN1	Q9GZT9	709
ING4	JADE3	Q92613	678
ING4	BRD1	O95696	677
ING4	HIF1A	Q16665	670
ING4	BRPF3	Q9ULD4	646

IntAct

83 interactions, top by confidence:

A	B	Type	Score
JADE2	ING4	psi-mi:“MI:0915”(physical association)	0.660
HNRNPD	ING4	psi-mi:“MI:0915”(physical association)	0.600
ING4	HNRNPD	psi-mi:“MI:0915”(physical association)	0.600
ING4	HNRNPD	psi-mi:“MI:0407”(direct interaction)	0.600
ING4	NAV2	psi-mi:“MI:0915”(physical association)	0.560
NAV2	ING4	psi-mi:“MI:0915”(physical association)	0.560
GRIPAP1	ING4	psi-mi:“MI:0915”(physical association)	0.560
JADE2	ING4	psi-mi:“MI:0915”(physical association)	0.560
BEX3	ING4	psi-mi:“MI:0915”(physical association)	0.560
GRN	ING4	psi-mi:“MI:0915”(physical association)	0.560
ING4		psi-mi:“MI:0915”(physical association)	0.560
ING4	PEX1	psi-mi:“MI:0915”(physical association)	0.560
ING4	WFS1	psi-mi:“MI:0915”(physical association)	0.560
ING4	RNF11	psi-mi:“MI:0915”(physical association)	0.560
ING4	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
HTT	ING4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (164): ING4 (Affinity Capture-Western), ING4 (Co-localization), NAV2 (Two-hybrid), ING4 (Affinity Capture-Western), TP53 (Reconstituted Complex), HNRNPD (Affinity Capture-Western), ING4 (Affinity Capture-Western), HNRNPD (Reconstituted Complex), MYC (Protein-RNA), TP53 (Affinity Capture-Western), HIST1H3A (Reconstituted Complex), ING4 (Reconstituted Complex), RELA (Reconstituted Complex), ING4 (Biochemical Activity), ING4 (Reconstituted Complex)

ESM2 similar proteins: A1Z7A6, B3H615, O13870, O42871, O43150, O74508, O74736, O94740, O97902, P30630, P38806, P50947, P62484, Q09459, Q10580, Q177A7, Q1AAU6, Q2UTN6, Q3T095, Q561X3, Q5AHB8, Q5AL52, Q5M8Y7, Q5XG48, Q5ZK36, Q5ZKY4, Q6BNL6, Q6C5V7, Q6CL17, Q6CXN0, Q6FQJ1, Q6FSB1, Q755J9, Q757W2, Q7QH62, Q7SIG6, Q7YZA2, Q8C0D7, Q8IQQ4, Q8WYH8

Diamond homologs: A3QMD7, O74736, P38806, Q08465, Q3T095, Q54PN9, Q5AHB8, Q5ZKY4, Q6BNL6, Q6C5V7, Q6CXN0, Q6FSB1, Q757W2, Q8C0D7, Q8WYH8, Q9D8Y8, Q9LIQ6, Q9UNL4, Q9VJY8, B3H615, O42871, P50947, Q498T3, Q5RBA1, Q5ZK36, Q66KD5, Q7ZX31, Q8VEK6, Q9NXR8, Q9QXV3, Q9UK53, Q9ESK4, Q9H160, P34447, Q5F489, Q5EAW9, Q5VWG9, A7MAZ4, O74508, Q03012

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RUNX3	“up-regulates quantity by expression”	ING4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
HATs acetylate histones	6	15.3×	2e-04
Oxidative Stress Induced Senescence	5	14.6×	2e-03
Chromatin modifying enzymes	5	11.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of DNA replication	5	44.7×	4e-05
nucleosome assembly	6	20.6×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1214 predictions. Top by Δscore:

Variant	Effect	Δscore
12:6651230:AAAAC:A	acceptor_gain	1.0000
12:6651231:AAAC:A	acceptor_gain	1.0000
12:6651233:AC:A	acceptor_gain	1.0000
12:6651234:CC:C	acceptor_gain	1.0000
12:6651235:C:CC	acceptor_gain	1.0000
12:6651235:CTG:C	acceptor_loss	1.0000
12:6651236:T:G	acceptor_loss	1.0000
12:6651241:C:CT	acceptor_gain	1.0000
12:6651242:A:T	acceptor_gain	1.0000
12:6651317:CACTT:C	donor_loss	1.0000
12:6651318:ACTTA:A	donor_loss	1.0000
12:6651319:CTTA:C	donor_loss	1.0000
12:6651320:TTACC:T	donor_loss	1.0000
12:6651321:TA:T	donor_loss	1.0000
12:6651322:ACCA:A	donor_loss	1.0000
12:6651382:AACAC:A	acceptor_loss	1.0000
12:6651383:ACAC:A	acceptor_loss	1.0000
12:6651384:CA:C	acceptor_gain	1.0000
12:6651384:CACTG:C	acceptor_loss	1.0000
12:6651385:ACTGG:A	acceptor_loss	1.0000
12:6651386:C:CC	acceptor_gain	1.0000
12:6651386:C:CG	acceptor_loss	1.0000
12:6651387:T:C	acceptor_loss	1.0000
12:6652269:A:AC	donor_gain	1.0000
12:6652270:C:CC	donor_gain	1.0000
12:6652270:CAT:C	donor_gain	1.0000
12:6652416:CTT:C	acceptor_gain	1.0000
12:6652423:A:C	acceptor_gain	1.0000
12:6652427:C:CT	acceptor_gain	1.0000
12:6652647:C:CA	donor_gain	1.0000

AlphaMissense

1661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:6651219:G:C	C242W	1.000
12:6651220:C:G	C242S	1.000
12:6651220:C:T	C242Y	1.000
12:6651221:A:G	C242R	1.000
12:6651221:A:T	C242S	1.000
12:6651228:G:C	C239W	1.000
12:6651229:C:A	C239F	1.000
12:6651229:C:G	C239S	1.000
12:6651229:C:T	C239Y	1.000
12:6651230:A:C	C239G	1.000
12:6651230:A:G	C239R	1.000
12:6651230:A:T	C239S	1.000
12:6651234:C:A	W237C	1.000
12:6651234:C:G	W237C	1.000
12:6651325:A:G	W237R	1.000
12:6651325:A:T	W237R	1.000
12:6651336:G:T	P233H	1.000
12:6651337:G:A	P233S	1.000
12:6651348:A:G	L229P	1.000
12:6651356:A:C	C226W	1.000
12:6651357:C:A	C226F	1.000
12:6651357:C:G	C226S	1.000
12:6651357:C:T	C226Y	1.000
12:6651358:A:C	C226G	1.000
12:6651358:A:G	C226R	1.000
12:6651358:A:T	C226S	1.000
12:6651362:A:C	F224L	1.000
12:6651362:A:T	F224L	1.000
12:6651363:A:C	F224C	1.000
12:6651363:A:G	F224S	1.000

dbSNP variants (sampled 300 via entrez): RS1000436566 (12:6662674 T>C), RS1001178801 (12:6649962 A>G), RS1001254100 (12:6653194 T>C), RS1001347935 (12:6656339 C>A), RS1001419425 (12:6663267 T>C,G), RS1001463927 (12:6656103 C>G,T), RS1001695472 (12:6649816 G>A), RS1001932749 (12:6663001 T>C,G), RS1002065929 (12:6664830 T>C), RS1002536974 (12:6664401 C>T), RS1003520645 (12:6661870 G>A,C), RS1003573071 (12:6661534 G>C), RS1003632570 (12:6650964 C>T), RS1003879452 (12:6658236 T>A), RS1003999736 (12:6654702 T>C)

Disease associations

OMIM: gene MIM:608524 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	7
Cisplatin	affects cotreatment, increases expression, decreases expression, increases reaction, increases activity	3
bisphenol A	increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
Air Pollutants	decreases expression, increases abundance	2
Estradiol	decreases expression	2
afuresertib	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
cupric chloride	decreases expression	1
cupric oxide	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
pinostrobin	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
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
(+)-JQ1 compound	increases expression	1
Leflunomide	decreases expression	1
Ethanol	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases expression	1
Cannabidiol	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer