ING3 (inhibitor of growth family, member 3)

2014-11-01   Audrey Mouche , Katherine Yaacoub , Thierry Guillaudeux , Rémy Pedeux 

INSERM U917, Microenvironnement et Cancer, Rennes, France, Universite de Rennes 1, Rennes, France (AM, KY, RP, TG); Etablissement Francais du Sang, Rennes, France (RP); UMS Biosit 3480 CNRS\\\/018 INSERM (TG)


Atlas Image
Figure 1. Chromosomal localization of the ING3 gene in Homo sapiens.


Atlas Image
Figure 2. Structure and transcripts of Human ING3 genes. Coding regions are in dark blue and non-coding regions are represented in light blue.


In 1996, Karl Riabowols group identified a new Tumor Suppressor Gene (TSG) by using subtractive hybridization between cDNAs from normal mammary epithelial cells and mammary epithelial cells from tumor. This experiment was followed by an in vivo screen for tumourigenesis. Using this method, the authors identified a new candidate TSG that they named ING1 for INhibitor of Growth 1 (Garkavtsev et al., 1996). Few years later, ING2, ING3, ING4 and ING5 were identified by homology search. ING3 was identified through bioinformatic analyses in order to find human EST clone showing a high homology with the p33ING1b and p33ING2 cDNAs (Nagashima et al., 2003).


The ING3 gene has been mapped to chromosome 7 at locus 7q31. Interestingly, unlike ING1, 2, 4 and 5, ING3 is located far from telomeric regions and is evolutionarily distinct from the other (Fig.1) (He et al., 2005). Human ING3 is made of twelve exons, resulting in 2 transcribed variants (ING3v1a, ING3v3) (Fig.2).


INGX is the pseudogene of ING (He et al., 2005).


Atlas Image
Figure 3. Schematic representation of ING3 proteins structure. In the C-terminal part: Nuclear Localization Signal (NLS), Plant Homeo Domain (PHD). In the N-terminal part: Leucine Zipper-Like domain (LZL), Novel Conserved Region (NCR).


The ING proteins are characterized by the presence of a highly conserved PHD in their C-terminal part. This domain is commonly found in proteins involved in chromatin modification (Bienz, 2006; Mellor, 2006). The C-terminal part of ING3 isoform contains a Leucine Zipper-Like domain (LZL) and a Novel Conserved Region (NCR) (Fig.3).


ING3 is ubiquitously expressed in mammalian tissues. Moreover, ING3 expression is increased in oocytes from Human, Rhesus monkey and mice (Awe and Byrne, 2013).


ING3 contains an NLS domain, so it is mainly located in the nucleus.


ING3 is a candidate tumor suppressor gene. ING3 regulates apoptosis in a p53 dependent and independent manner. Indeed, ING3 activates bax transcription through p53 and promotes apoptosis via Fas/caspase 8 pathway in melanoma cells (Nagashima et al., 2003; Wang and Li, 2006). Moreover, ING3 is a member of the human NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of genes through acetylation of histones H4 and H2A (Doyon et al., 2004). ING3 through its involvement in the NuA4 HAT complex regulates the expression of mTOR. Consequently, ING3 regulates oocyte polarization and asymmetric division during oocyte mice maturation through the mTOR pathway (Suzuki et al., 2013).

Implicated in

Entity name
The analysis of LOH (loss of heterozygosity) for ING genes family, in 33 samples of ameloblastoma cases, showed a high percentage of allelic loss (48.5%) for ING3 gene. Moreover, there is a strong correlation between the inactivation of ING3 gene and tumor aggressiveness (Borkosky et al., 2010).
Entity name
Breast cancer
The analysis of ING3 status in 9 breast cancer cell lines revealed a downregulation of ING3v1 and v3 mRNA in 2 of these cell lines. However, their mRNA abundances were increased in seven other cell lines compared to normal breast epithelial cells (Walzak et al., 2008).
Entity name
Colorectal carcinoma
In colorectal carcinoma, the ING3 mRNA expression was reduced compared to colorectal non-neoplastic mucosa (NNM). In addition, the expression of ING3 protein has been detected in the cytoplasm but not in the nucleus. Moreover, there is no difference of ING3 protein level between NNM and carcinomas tissues. However, the expression of ING3 was not correlated to the prognosis of patients with colorectal cancer. These results suggest that downregulation of ING3 may have a significant role in colorectal carcinogenesis (Gou et al., 2014).
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Cutaneous melanoma
In malignant melanoma, nuclear expression of ING3 was reduced compared to dysplastic nevi, while an increase of cytoplasmic expression is found, in 24%, 39%, and 62% of the dysplastic nevi, primary melanoma, and metastases, respectively. In addition, the location of primary melanomas and the upregulated ING3 cytoplasmic expression are not correlated. In patients with strong nuclear ING3 staining, the survival rate reached 93%, whereas in patients with negative-to-moderate nuclear ING3 staining, the survival rate was just 44%. These findings suggest that ING3 is an important factor for melanoma prognosis and progression (Wang et al., 2007).
Entity name
Head and neck squamous carcinoma
The analysis of loss of heterozygosity in 49 head and neck squamous cell carcinoma (HNSCC) showed that 48% had an allelic deletion detected in 2 regions on chromosome 7q31 where ING3 is mapped. In addition, only one sample showed a missense mutation manifested by nucleotide change from GAC to GGC at codon 20 which leads to an amino acid substitution from aspartic acid to glycine. A silent mutation from GAC to GAT has been detected in three samples at codon 356 with no amino acid change. Moreover, 50% of primary tumor tissues and 75% of tumor derived cell lines showed a decreased expression of ING3 mRNA. In one case, a complete loss of ING3 mRNA has been detected in 2 primary tissues. In this study, a significant decrease of ING3 mRNA expression but rare mutation found, suggests that a transcriptional mechanism, such as promoter methylation, may contribute to the HNSCC development (Gunduz et al., 2002).
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Hepatocellular carcinoma
In the case of hepatocellular carcinoma (HCC), the analysis of ING3 mRNA expression revealed that in all the 49 tumor samples, ING3 was downregulated compared to normal livers. In addition, the expression of ING3 mRNA is reduced in 18 HCC cell lines compared to noncancerous cell lines. Moreover, in 64/112 samples of HCC, a downregulation of ING3 protein expression was found, while 24/112 samples had an upregulation of ING3 and 24/112 exhibited the same expression of ING3 protein. However, the overexpression of ING3 suppresses cell proliferation in Hep3B cell line, thus confirming that ING3 may be tumor suppressor gene (Lu et al., 2012). Another study showed that 16/20 patients with HCC exhibited a downregulation of ING3 protein and ING3 mRNA expression. In addition, in 4/6 hepatic cell lines, there is a downregulation of ING3 protein and ING3 mRNA expression (Yang et al., 2012).
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Lung cancer
In two lung cancer cell lines, a downregulation of ING3v1 and v3 transcripts has been detected (Walzak et al., 2008).
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Ovarian cancer
ING3v1 and ING3v3 showed a weak decrease of mRNA expression, in 1/1 ovarian cancer cell line GI-102 (Walzak et al., 2008).
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Pancreatic cancer
In GI-103 pancreatic cell line, mRNA expression of ING3v3 transcript is downregulated but, surprisingly, ING3v1 is upregulated (Walzak et al., 2008).
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Prostate cancer
In PC3 prostate cancer cell line, mRNA expression levels of ING3v1 and v3 are decreased (Walzak et al., 2008).


Pubmed IDLast YearTitleAuthors
234581642013Identifying candidate oocyte reprogramming factors using cross-species global transcriptional analysis.Awe JP et al
162976272006The PHD finger, a nuclear protein-interaction domain.Bienz M et al
206814102010Allelic loss of the ING gene family loci is a frequent event in ameloblastoma.Borkosky SS et al
149662702004Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans.Doyon Y et al
89440211996Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation.Garkavtsev I et al
249273422014Downregulated inhibitor of growth 3 (ING3) expression during colorectal carcinogenesis.Gou WF et al
120804762002Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers.Gunduz M et al
153562802005Phylogenetic analysis of the ING family of PHD finger proteins.He GH et al
228079582012Downregulation of inhibitor of growth 3 is correlated with tumorigenesis and progression of hepatocellular carcinoma.Lu M et al
168398702006It takes a PHD to read the histone code.Mellor J et al
125451552003A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis.Nagashima M et al
240661522013ING3 is essential for asymmetric cell division during mouse oocyte maturation.Suzuki S et al
177201552008Expression profiles of mRNA transcript variants encoding the human inhibitor of growth tumor suppressor gene family in normal and neoplastic tissues.Walzak AA et al
176345372007Prognostic significance of nuclear ING3 expression in human cutaneous melanoma.Wang Y et al
165203802006ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells.Wang Y et al
225503372012Expression and prognostic value of ING3 in human primary hepatocellular carcinoma.Yang HY et al

Other Information

Locus ID:

NCBI: 54556
MIM: 607493
HGNC: 14587
Ensembl: ENSG00000071243


dbSNP: 54556
ClinVar: 54556
TCGA: ENSG00000071243


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
HATs acetylate histonesREACTOMER-HSA-3214847

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
194016822010High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.52
125451552003A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis.47
120804762002Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers.27
176345372007Prognostic significance of nuclear ING3 expression in human cutaneous melanoma.23
180818762008Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer.16
199357012010The tumor suppressor ING3 is degraded by SCF(Skp2)-mediated ubiquitin-proteasome system.11
258197532015ING3 protein expression profiling in normal human tissues suggest its role in cellular growth and self-renewal.8
272818242016Mechanism of Histone H3K4me3 Recognition by the Plant Homeodomain of Inhibitor of Growth 3.8
249273422014Downregulated inhibitor of growth 3 (ING3) expression during colorectal carcinogenesis.7
293816812018Human ex vivo prostate tissue model system identifies ING3 as an oncoprotein.5


Audrey Mouche ; Katherine Yaacoub ; Thierry Guillaudeux ; Rémy Pedeux

ING3 (inhibitor of growth family, member 3)

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

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