ING2

Gene Summary

Gene:ING2; inhibitor of growth family member 2
Aliases: ING1L, p33ING2
Location:4q35.1
Summary:This gene is a member of the inhibitor of growth (ING) family. Members of the ING family associate with and modulate the activity of histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes and function in DNA repair and apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:inhibitor of growth protein 2
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ING2 (cancer-related)

Zhang R, Jin J, Shi J, Hou Y
INGs are potential drug targets for cancer.
J Cancer Res Clin Oncol. 2017; 143(2):189-197 [PubMed] Related Publications
PURPOSE: The inhibitor of growth (ING) family consists of ING1, ING2, ING3, ING4 and ING5, which function as the type II tumor suppressors. INGs regulate cell proliferation, senescence, apoptosis, differentiation, angiogenesis, DNA repair, metastasis, and invasion by multiple pathways. In addition, INGs increase cancer cell sensitivity for chemotherapy and radiotherapy, while clinical observations show that INGs are frequently lost in some types of cancers. The aim of the study was to summarize the recent progress regarding INGs regulating tumor progression.
METHODS: The literatures of INGs regulating tumor progression were searched and assayed.
RESULTS: The regulating signaling pathways of ING1, ING2, ING3 or ING4 on tumor progression were shown. The mechanisms of INGs on tumor suppression were also assayed.
CONCLUSIONS: This review better summarized the signaling mechanism of INGs on tumor suppression, which provides a candidate therapy strategy for cancers.

Temel M, Turkmen A, Dokuyucu R, et al.
A novel tumor suppressor gene in basal cell carcinoma: inhibition of growth factor-2.
Tumour Biol. 2015; 36(6):4611-6 [PubMed] Related Publications
In loss of heterozygosity (LOH) studies at the chromosome 4q22-35 region, it was shown that the amount of deletion was high in basal cell carcinoma (BCC). It has been proposed that genes located in this chromosomal region could be tumor suppressor genes in BCC. It has been thought that deletions in the ING2 gene located in the same region can play a role in the pathophysiology of BCC and that deletions occurring in this region may influence the level of ING2 expression in BCC. Tumoral and non-tumoral tissues from 75 patients with BCC (45 men and 30 women) were included to the study. Lesions were excised by a surgical margin of 0.5 cm. After excision, RNA was isolated from tumoral and non-tumoral tissue samples. ING2 messenger RNA (mRNA) expression level was determined in tumoral and non-tumoral tissues by the real-time polymerase chain reaction (RT-PCR). It was detected that ING2 mRNA expression level decreased in tumoral tissues when compared to non-tumoral tissues from BCC patients (p = 0.0001). It was found that expression levels of this gene were comparable among patients with primary, recurrent, or multiple BCC. It is thought that ING2 gene expression level could contribute to the development of BCC but not be associated with the stage and the prognosis of the tumor.

Han XR, Bai XZ, Sun Y, Yang Y
Nuclear ING2 expression is reduced in osteosarcoma.
Oncol Rep. 2014; 32(5):1967-72 [PubMed] Related Publications
Osteosarcoma is a high-grade malignant bone tumor. Loss of inhibitor of growth 2 (ING2) expression has been demonstrated in numerous types of cancers. However, no study has shown the relationship between ING2 expression and osteosarcoma. In the present study, we confirmed that the levels of ING2 mRNA and protein were lower in cancer tissues than these levels in normal tissues. Loss of nuclear ING2 protein was significantly associated with a decreased survival time of patients. Osteosarcoma cells were transfected with ING2 protein without a nuclear localization signal or intact ING2 protein to examine the effects of exogenous expression of ING2 in vitro. Compared to the control cells, intact ING2-expressing cells exhibited increased apoptosis, G1 phase arrest and senescence. Taken together, these results suggest that ING2 acts as a tumor suppressor in osteosarcoma.

Sardiu ME, Smith KT, Groppe BD, et al.
Suberoylanilide hydroxamic acid (SAHA)-induced dynamics of a human histone deacetylase protein interaction network.
Mol Cell Proteomics. 2014; 13(11):3114-25 [PubMed] Free Access to Full Article Related Publications
Histone deacetylases (HDACs) are targets for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor approved by the U.S. Food and Drug Administration for the treatment of cutaneous T-cell lymphoma. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. We then assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2's association with the complex. Our dynamic protein interaction network resource provides novel insights into the molecular mechanism of SAHA action and demonstrates the potential for drugs to rewire networks.

Pan YQ, Zhang X, Xu DP, et al.
Decreased expression of ING2 gene and its clinicopathological significance in Chinese NSCLC patients.
Neoplasma. 2014; 61(4):468-75 [PubMed] Related Publications
The inhibitor of growth 2 (ING2) is a member of lNG family, involved in cell cycle regulation, DNA repair, apoptosis and senescence, and participating in chromatin remodeling and transcriptional regulation by histone modification. Recent researches suggest ING2 plays roles in carcinogenesis both as tumor suppressor gene and ongocene depending on tumor types and cell status. Here, we investigated the status of ING2 in a series of 64 Chinese non-small cell lung cancer (NSCLC)patients using immunohistochemistry (IHC) and confirmed the results with Western blotting. RT-PCR results revealed the expression level of ING2 was consistent with mRNA level. The IHC results showed that ING2 protein expression was significantly decreased in NSCLC samples compared with normal lung tissues (P

Zhong J, Yang L, Liu N, et al.
Knockdown of inhibitor of growth protein 2 inhibits cell invasion and enhances chemosensitivity to 5-FU in human gastric cancer cells.
Dig Dis Sci. 2013; 58(11):3189-97 [PubMed] Related Publications
BACKGROUND: The inhibitor of growth (ING) family is involved in multiple cellular functions, but the role of ING2 in gastric cancer progression is unclear.
AIM: To investigate the effects of ING2 gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in human gastric cancer cells and its possible mechanisms.
METHODS: Short hairpin RNA (shRNA) targeting ING2 (shING2) was transfected into MGC-803 cells using Lipofectamine 2000, and stable transfection cell lines were established using G418. Cell viability, cell cycle distribution, cell apoptosis, and invasive ability were measured to determine the influence of ING2 knockdown on cell biologic characteristics. Messenger RNA (mRNA) and protein levels of ING2, cyclin D1, NF-kappaB/p65, and several matrix metalloproteinases (MMPs) were determined by use of real-time polymerase chain reaction (PCR) or Western blotting, respectively.
RESULTS: Our results showed that ING2 knockdown induced cell apoptosis and inhibited cell viability significantly (P < 0.05). Additionally, ING2 knockdown induced a specific G0/G1 arrest. Furthermore, the suppression of ING2 could enhance the chemosensitivity of gastric cancer cells to 5-FU significantly. Moreover, knockdown of ING2 expression significantly reduced cellular metastatic ability and expression of MMPs in MGC-803 cells. The expression of cyclin D1 and NF-kappaB/p65 was also markedly inhibited in MGC-803/shING2 cells compared with control cells.
CONCLUSIONS: ING2 not only plays an essential role in the growth and invasion of MGC-803 cells but also represents a potential approach to chemosensitization therapy in human gastric cancer.

Xing J, Dinney CP, Shete S, et al.
Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer.
Cancer. 2012; 118(1):205-15 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date.
METHODS: In this study, the authors applied a comprehensive pathway-based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case-control study that included 803 bladder cancer cases and 803 controls.
RESULTS: In total, 17 SNPs were associated significantly with altered bladder cancer risk (P < .05), of which, 7 SNPs retained noteworthiness after they were assessed with a Bayesian approach for the probability of false discovery. The most noteworthy SNP was reference SNP 11132186 (rs11132186) in the inhibitor of growth family, member 2 (ING2) gene. Compared with the major allele-containing genotypes, the odds ratio was 0.52 (95% confidence interval, 0.32-0.83; P = .005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene-smoking interactions were observed for 3 of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, potential gene-gene interactions were identified.
CONCLUSIONS: In this a large association study of the NER pathway and the risk of bladder cancer, several novel predisposition variants were identified along with potential gene-gene and gene-environment interactions in modulating bladder cancer risk. The results reinforce the importance of a comprehensive, pathway-focused, and tagging SNP-based candidate gene approach to identify low-penetrance cancer susceptibility loci.

Saito M, Kumamoto K, Robles AI, et al.
Targeted disruption of Ing2 results in defective spermatogenesis and development of soft-tissue sarcomas.
PLoS One. 2010; 5(11):e15541 [PubMed] Free Access to Full Article Related Publications
ING2 (inhibitor of growth family, member 2) is a member of the plant homeodomain (PHD)-containing ING family of putative tumor suppressors. As part of mSin3A-HDAC corepressor complexes, ING2 binds to tri-methylated lysine 4 of histone H3 (H3K4me3) to regulate chromatin modification and gene expression. ING2 also functionally interacts with the tumor suppressor protein p53 to regulate cellular senescence, apoptosis and DNA damage response in vitro, and is thus expected to modulate carcinogenesis and aging. Here we investigate the developmental and physiological functions of Ing2 through targeted germline disruption. Consistent with its abundant expression in mouse and human testes, male mice deficient for Ing2 showed abnormal spermatogenesis and were infertile. Numbers of mature sperm and sperm motility were significantly reduced in Ing2(-/-) mice (∼2% of wild type, P<0.0001 and ∼10% of wild type, P<0.0001, respectively). Their testes showed degeneration of seminiferous tubules, meiotic arrest before pachytene stage with incomplete meiotic recombination, induction of p53, and enhanced apoptosis. This phenotype was only partially abrogated by concomitant loss of p53 in the germline. The arrested spermatocytes in Ing2(-/-) testes were characterized by lack of specific HDAC1 accumulation and deregulated chromatin acetylation. The role of Ing2 in germ cell maturation may extend to human ING2 as well. Using publicly available gene expression datasets, low expression of ING2 was found in teratozoospermic sperm (>3-fold reduction) and in testes from patients with defective spermatogenesis (>7-fold reduction in Sertoli-cell only Syndrome). This study establishes ING2 as a novel regulator of spermatogenesis functioning through both p53- and chromatin-mediated mechanisms, suggests that an HDAC1/ING2/H3K4me3-regulated, stage-specific coordination of chromatin modifications is essential to normal spermatogenesis, and provides an animal model to study idiopathic and iatrogenic infertility in men. In addition, a bona fide tumor suppressive role of Ing2 is demonstrated by increased incidence of soft-tissue sarcomas in Ing2(-/-) mice.

Pot I, Ikeuchi Y, Bonni A, Bonni S
SnoN: bridging neurobiology and cancer biology.
Curr Mol Med. 2010; 10(7):667-73 [PubMed] Free Access to Full Article Related Publications
The transcriptional regulator SnoN has been the subject of growing interest due to its diverse functions in normal and pathological settings. A large body of evidence has established a fundamental role for SnoN as a modulator of signaling and responses by the transforming growth beta (TGFbeta) family of cytokines, though how SnoN regulates TGFbeta responses remains incompletely understood. In accordance with the critical and complex roles of TGFbeta in tumorigenesis and metastasis, SnoN may act as a tumor promoter or suppressor depending on the stage and type of cancer. Beyond its role in cancer, SnoN has also been implicated in the control of axon morphogenesis in postmitotic neurons in the mammalian brain. Remarkably, signaling pathways that control SnoN functions in the divergent cycling cells and postmitotic neurons appear to be conserved. Identification of novel SnoN regulatory and effector mechanisms holds the promise of advances at the interface of cancer biology and neurobiology.

Zhang H, Ma H, Wang Q, et al.
Analysis of loss of heterozygosity on chromosome 4q in hepatocellular carcinoma using high-throughput SNP array.
Oncol Rep. 2010; 23(2):445-55 [PubMed] Related Publications
To identify tumour suppressor genes (TSGs) associated with hepatocellular carcinoma (HCC) on chromosome 4q using a high-throughput single nucleotide polymorphism (SNP) array, we first scanned for loss of heterozygosity (LOH) of 40 SNPs on chromosome 4q and discovered 2 hot regions: 4q24-26 and 4q34.3-35. We then further scanned for LOH of 338 SNPs in genes around 4q34.3-35 and discovered 3 genes with the most frequent LOH: nei endonuclease VIII-like 3 (NEIL3), interferon regulatory factor 2 (IRF2) and inhibitor of growth family member 2 (ING2). A review of the literature indicates only ING2 might be a TSG associated with HCC.

Ythier D, Brambilla E, Binet R, et al.
Expression of candidate tumor suppressor gene ING2 is lost in non-small cell lung carcinoma.
Lung Cancer. 2010; 69(2):180-6 [PubMed] Related Publications
ING2 is a candidate tumor suppressor gene involved in cell cycle control, apoptosis and senescence. Furthermore, we have recently shown that loss of ING2 expression is associated with increased genome instability. We investigated its status in a series of 120 non-small cell lung cancer (NSCLC) by using immunohistochemistry (IHC). The results showed that ING2 protein expression is downregulated in more than 50% of NSCLC, with a higher frequency in adenocarcinoma (ADK) as compared to squamous cell carcinoma (SCC) (68% versus 45%, P=0.021). Loss of ING2 expression occurs in a high proportion of tumors from stage I and was not associated with patient's gender, age and 5-year survival. When investigating the possible mechanisms responsible for the decrease of ING2 expression, we did not observe any loss of heterozygosity or mutation in the ING2 gene. However, in 95% of the cases examined, we identified a silent single nucleotide polymorphism (SNP). By using quantitative RT-PCR, we found that ING2 loss of expression may be due to the decrease of its mRNA level. Analysis of CpG islands present in the promoter region of the ING2 gene did not allow for the detection of methylation. Mechanistically, although p53 can regulate ING2 transcription and ING2 enhances p53 activity, no correlation between ING2 and p53 IHC status was observed. Overall, these results indicate that loss of ING2 expression could contribute to lung tumorigenesis independently of p53.

Unoki M, Kumamoto K, Harris CC
ING proteins as potential anticancer drug targets.
Curr Drug Targets. 2009; 10(5):442-54 [PubMed] Free Access to Full Article Related Publications
Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies.

Kumamoto K, Fujita K, Kurotani R, et al.
ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression.
Int J Cancer. 2009; 125(6):1306-15 [PubMed] Free Access to Full Article Related Publications
Inhibitor of growth 2 (ING2) is associated with chromatin remodeling and regulation of gene expression by binding to a methylated histone H3K4 residue and recruiting HDAC complexes to the region. The aim of our study is to investigate the regulation of ING2 expression and the clinical significance of upregulated ING2 in colon cancer. Here, we show that the ING2 mRNA level in colon cancer tissue increased to more than twice than that in normal mucosa in the 45% of colorectal cancer cases that we examined. A putative NF-kappaB binding site was found in the ING2 promoter region. We confirmed that NF-kappaB could bind to the ING2 promoter by EMSA and luciferase assays. Subsequent microarray analyses revealed that ING2 upregulates expression of matrix metalloproteinase 13 (MMP13), which enhances cancer invasion and metastasis. ING2 regulation of MMP13 expression was confirmed in both ING2 overexpression and knock down experiments. MMP13 expression was further induced by coexpression of ING2 with HDAC1 or with mSin3A, suggesting that the ING2-HDAC1-mSin3A complex members regulates expression of MMP13. In vitro invasion assay was performed to determine functional significance of ING2 upregulation. ING2 overexpressed cells exhibited greater invasive potential. Taken together, upregulation of ING2 was associated with colon cancer and MMP13-dependent cellular invasion, indicating that ING2 expression might be involved with cancer invasion and metastasis.

Borkosky SS, Gunduz M, Nagatsuka H, et al.
Frequent deletion of ING2 locus at 4q35.1 associates with advanced tumor stage in head and neck squamous cell carcinoma.
J Cancer Res Clin Oncol. 2009; 135(5):703-13 [PubMed] Related Publications
BACKGROUND: Loss of heterozygosity (LOH) in the ING family members has been shown in head and neck squamous cell carcinoma (HNSCC) except for ING2. Like all the other members of ING family, ING2, which is located at chromosome 4q35.1, is a promising tumor suppressor gene (TSG). In this study, we performed LOH analysis of ING2 in HNSCC and compared it with clinicopathological variables.
MATERIALS AND METHODS: We performed LOH analysis in DNAs from 80 paired of normal and HNSCC tissues, using a specifically designed microsatellite marker on chromosome 4q35.1, which detects allelic loss of ING2. TP53 mutation analysis and its relationship with ING2 chromosomal deletion were also performed in available 68 of the samples. The correlation between LOH status and clinicopathological characteristics was evaluated by using statistical methods. The overall survival (OS) and disease free survival (DFS) were also determined.
RESULTS: LOH was detected in 54.6% (30/55) of the informative samples. Statistical significance was obtained between LOH and tumor (T) stage (P = 0.02), application of radiotherapy and chemotherapy. Positive node status (N) appeared to be the only independent prognostic factor for both OS (P = 0.031) and DFS (P = 0.044).
CONCLUSIONS: Our study showed allelic loss of 4q35.1 in HNSCC. The high percentage of LOH suggests ING2 as a candidate TSG in HNSCC. High LOH frequency was statistically associated with advanced T stage, suggesting that ING2 LOH might occur in late stages during HNSCC progression.

Ythier D, Larrieu D, Brambilla C, et al.
The new tumor suppressor genes ING: genomic structure and status in cancer.
Int J Cancer. 2008; 123(7):1483-90 [PubMed] Related Publications
The Inhibitor of Growth 1 (ING1) gene has been identified and characterized as a Type-II tumor suppressor gene (TSG). Subsequently, 4 additional members of the family were identified by homology search. ING proteins contain a nuclear localization sequence (NLS) and a plant homeo domain (PHD) finger motif in their C-terminus. These proteins are involved in numerous signaling pathways especially in 2 tumor suppressor pathways: apoptosis and senescence. In human tumors, several studies have shown that the expression of ING1 is frequently lost or downregulated. It occurs most frequently at the RNA level, and thus epigenetics mechanism could be involved. We summarize the current knowledge on ING proteins functions and their involvement in various signaling pathways. We also review the studies that have investigated the ING protein status in human tumors. The interest of ING proteins as biomarkers and their role in tumor initiation and progression is discussed.

Gunduz M, Gunduz E, Rivera RS, Nagatsuka H
The inhibitor of growth (ING) gene family: potential role in cancer therapy.
Curr Cancer Drug Targets. 2008; 8(4):275-84 [PubMed] Related Publications
The discovery of ING1 gene paved the way to the identification of other ING members (ING2-5) and their isoforms associated with cell cycle, apoptosis and senescence. The ING family has been an emerging putative tumor suppressor gene (TSG) in which the major mechanism is through interaction with the determinants of chromatin function and gene-specific transcription factors. The regulatory mechanism highly involves the conserved plant homeodomain (PHD), which binds to histones in a methylation-sensitive manner, suggesting that ING proteins may contribute to the maintenance of the epigenetic code. Furthermore, ING family members contain nuclear localization signals and N-terminal sequences important in the interaction with histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) that regulate gene promoter activity within chromatin. Although ING proteins have the same PHD motif, the variation in the N-terminal dictates the differences in tumor the suppressive ability of ING in various tumors. Inactivation of the normal function is achieved through allelic loss of genomic regions containing the ING gene, alteration in the ING promoter region, variation of mRNA splicing efficacy or reduced mRNA stability. It is most probably the apparent combination of these aberrant mechanisms that resulted in reduced availability of functional ING protein. In cancer cells, ING transcript levels are often suppressed but the genes are rarely mutated. The mechanism of suppression of ING expression may have to do with the abnormally high methylation levels of the ING gene promoter, which have been correlated with low transcript levels. Emerging evidence on the function of ING and related regulatory mechanisms strongly points to ING as a candidate TSG and therefore a potential target in the molecular therapy of some types of tumor.

Cetin E, Cengiz B, Gunduz E, et al.
Deletion mapping of chromosome 4q22-35 and identification of four frequently deleted regions in head and neck cancers.
Neoplasma. 2008; 55(4):299-304 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) is a diverse group of cancers that are frequently aggressive in their biologic behavior. Inactivation of tumor suppressor gene (TSG) is one of the most critical steps leading to HNSCC. Loss of heterozygosity analysis is very sensitive method for the detection of frequent allelic loss in a chromosomal locus. This method has been considered as an important evidence for the localization of TSGs. We analyzed loss of heterozygosity (LOH) at chromosome 4q22-35 region by using 14 polymorphic microsatellite markers in 83 matched normal and HNSCC tissues. LOH was detected at least in one location in 71 of 83 (86%) tumor tissues. Frequent deletions were detected at the location of microsatellite markers, D4S2909 (46%), D4S2623 (51%), D4S406 (48%), D4S1644 (45%) and D4S2979 (40%). Four different frequently deleted regions at 4q22, 4q25, 4q31 and 4q34-35 were observed. These regions include several putative TSGs such as Caspase-6, SMARCAD1, SMARCA5, SAP30 and ING2. Further molecular analysis of each gene should be performed to clarify their roles in head and neck squamous cell carcinogenesis.

Zhang HK, Pan K, Wang H, et al.
Decreased expression of ING2 gene and its clinicopathological significance in hepatocellular carcinoma.
Cancer Lett. 2008; 261(2):183-92 [PubMed] Related Publications
The inhibitor of growth (ING) family member 2 (ING2) is a newly discovered member of ING family that can regulate a wide range of cellular processes including cell growth arrest, apoptosis, and DNA repair. Researches have shown that ING2 can activate p53 and p53-mediated apoptotic pathway involved in the hepatocarcinogenesis. To investigate the role of ING2 in hepatocellular carcinoma (HCC) pathogenesis, we analyzed the correlations between the ING2 expression level and clinicopathologic factors and studied its prognostic role in primary HCC. Using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot, ING2 transcription and post-transcription level was found to be downregulated in the majority of tumors compared with matched non-tumors liver tissues (p=0.004 and p=0.014, respectively). The immunohistochemistry data indicated significant reduction of ING2 expression level in 44 of 84 (52.4%) HCC cases. In addition, the expression level of ING2 correlated with tumor size, histopathologic classification, serum AFP (p<0.05). Kaplan-Meier curves demonstrated that patients with reduced ING2 expression were at significantly increased risk for shortened survival time (p=0.009). Using multivariate analysis, ING2 expression was found to be an independent prognostic factor. Our data suggest that ING2 is involved in the progression of HCC, therefore it is considered to be a candidate tumor suppressor gene and its significantly decreased expression in HCC may lead to an unfavorable prognosis.

Wang Y, Li G
ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells.
J Biol Chem. 2006; 281(17):11887-93 [PubMed] Related Publications
The novel ING tumor-suppressor family proteins (ING1-5) have been discovered during the past decade and are recognized as the regulators of transcription, cell cycle checkpoints, DNA repair, apoptosis, cellular senescence, angiogenesis, and nuclear phosphoinositide signaling. ING proteins contain a few conserved domains, including plant homeodomain motif, nuclear localization signal, and potential chromatin regulatory domain, suggesting that the ING family proteins may share common biological functions. ING3 has been shown to modulate p53-mediated transcription, cell cycle control, and apoptosis, possibly by modulating the NuA4 complex histone acetyltransferase activity. Because ING1b and ING2 have been shown to be involved in cellular stress responses such as nucleotide excision repair and apoptosis after UV irradiation, we investigated whether ING3 also mediated UV-induced apoptosis. We found that ING3 expression was rapidly induced by UV irradiation at both mRNA and protein levels. Using the stable clones of melanoma cells overexpressing ING3, we showed that overexpression of ING3 significantly promoted UV-induced apoptosis. Unlike its homologues ING1b and ING2, ING3-increased apoptosis was independent of functional p53. Furthermore, ING3 did not affect the expression of mitochondrial proteins but increased the cleavage of Bid and caspases-8, -9, and -3. Moreover, ING3-mediated apoptosis was blocked by inhibition of caspase-8 or Fas activation. In addition, ING3 up-regulated Fas expression at both mRNA and protein levels. Knock down of ING3 decreased UV-induced apoptosis remarkably. These data indicate that ING3 plays an important role in cellular response to UV irradiation by enhancing UV-induced apoptosis through the activation of Fas/caspase-8 pathway.

Wang J, Chin MY, Li G
The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation.
Cancer Res. 2006; 66(4):1906-11 [PubMed] Related Publications
p33ING2 is a novel candidate tumor suppressor, which has been shown to be involved in the regulation of gene transcription, cell cycle arrest, and apoptosis in a p53-dependent manner for maintaining the genomic stability. Previously, we showed that p33ING2 promoted UV-induced apoptosis in human melanoma cells. To further reveal the role of p33ING2 in cellular stress response to UV irradiation, we hypothesized that p33ING2 may enhance the repair of UV-damaged DNA, similarly to its homologue p33(ING1b). Using the host-cell reactivation assay, we show that overexpression of p33ING2 significantly enhances nucleotide excision repair of UV-induced DNA damage in melanoma cells in a p53-dependent manner. Furthermore, DNA repair is completely abolished in cells treated with p33ING2 small interfering RNA, suggesting that a physiologic level of p33ING2 is required for nucleotide excision repair. In addition, we found that p33ING2 is an essential factor for UV-induced rapid histone H4 acetylation, chromatin relaxation, and the recruitment of damage recognition protein, xeroderma pigmentosum group A protein, to the photolesions. These observations suggest that p33ING2 is required for the initial DNA damage sensing and chromatin remodeling in the nucleotide excision repair process.

Okano T, Gemma A, Hosoya Y, et al.
Alterations in novel candidate tumor suppressor genes, ING1 and ING2 in human lung cancer.
Oncol Rep. 2006; 15(3):545-9 [PubMed] Related Publications
The ING1 gene is involved in the regulation of the cell cycle, senescence, and apoptosis and is a novel candidate tumor suppressor gene. ING2, another gene in the ING family, was identified and cloned. The functions of ING1 and ING2 largely depend on the activity of p53. To determine whether an alteration in these genes plays a role in carcinogenesis and tumor progression in lung cancer, we screened 30 human lung cancer cell lines and 31 primary lung cancer tumors for mutations in these genes using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct sequencing. Our findings failed to uncover any mutations in these genes. We also examined the expression of ING1 and ING2 in lung cancer cell lines that either had or lacked a p53 mutation, and in a control bronchial epithelium cell line, using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). ING1 expression was up-regulated in all 7 lung cancer cell lines that had a p53 mutation, while the expression of ING2 was down-regulated in 6 of 7 lung cancer cell lines that had a p53 mutation. These results suggest that the ING1 and ING2 genes have different roles in lung carcinogenesis and progression, and the ING2 gene may be an independent tumor suppressor candidate on p53.

Chin MY, Ng KC, Li G
The novel tumor suppressor p33ING2 enhances UVB-induced apoptosis in human melanoma cells.
Exp Cell Res. 2005; 304(2):531-43 [PubMed] Related Publications
The roles of p33ING2 as a tumor suppressor candidate have been shown through regulation of gene transcription, induction of cell cycle arrest, and apoptosis. As p33ING2 shares 58.9% homology with p33ING1b, we hypothesized that p33ING2 shares functional similarities with p33ING1b. We previously found that p33ING1b cooperates with p53 to enhance UVB-induced apoptosis. Here, we report that overexpression of p33ING2 enhanced apoptosis in UVB-irradiated and non-irradiated melanoma MMRU cells. We demonstrate that enhancement of apoptosis by p33ING2 requires the presence of functional p53. Furthermore, we found that overexpression of p33ING2 significantly downregulated the expression of Bcl-2 after UVB irradiation, resulting in an increased Bax/Bcl-2 ratio. Moreover, we found that p33ING2 promoted Bax translocation to mitochondria, altered the mitochondrial membrane potential, and induced cytochrome c release and thus the activation of caspases 9 and 3. In addition, we showed that under non-stress conditions p33ING2 upregulates Fas expression and activates caspase 8. Taken together, we demonstrate that p33ING2 cooperates with p53 to regulate apoptosis via activation of both the mitochondrial/intrinsic and death-receptor/extrinsic apoptotic pathways.

Gong W, Suzuki K, Russell M, Riabowol K
Function of the ING family of PHD proteins in cancer.
Int J Biochem Cell Biol. 2005; 37(5):1054-65 [PubMed] Related Publications
The ING genes encode a family of at least seven proteins with conserved plant homeodomain (PHD)-type zinc fingers in their C-termini. The founding member, ING1, is capable of binding to and affecting the activity of histone acetyltransferase (HAT), histone deacetylase (HDAC), and factor acetyltransferase (FAT) protein complexes. Some ING proteins are involved in transcriptional regulation of genes, such as the p53-inducible genes p21 and Bax. Others have been found to affect post-translational modifications, exemplified by the ING2-induced acetylation of p53 on the same site deacetylated by the Sir2 HDAC. Upon UV irradiation, ING1 causes cell cycle arrest and interacts with proliferating cell nuclear antigen to promote DNA repair or induce apoptosis in cells to prevent tumorigenesis depending upon the severity of DNA damage. It is very likely that, by linking DNA repair, apoptosis and chromatin remodeling to the transcriptional regulation of critical genes, ING1 exerts it tumor suppressor functions by helping maintain genomic stability. Therefore, ING proteins, which are down-regulated in a broad variety of cancer types, are able to restrict cell growth and proliferation, induce apoptosis, and modulate cell cycle progression, which strongly supports the notion that ING family proteins act as class II tumor suppressors.

Sironi E, Cerri A, Tomasini D, et al.
Loss of heterozygosity on chromosome 4q32-35 in sporadic basal cell carcinomas: evidence for the involvement of p33ING2/ING1L and SAP30 genes.
J Cutan Pathol. 2004; 31(4):318-22 [PubMed] Related Publications
BACKGROUND: Studies on basal cell carcinoma (BCC) have demonstrated that patched gene and p53 gene located at 9q22.3 and 17p13 are the main genes responsible for the onset of this tumor. In order to identify a possible involvement of other tumor suppressor genes, we screened 19 cases of BCCs for loss of heterozygosity (LOH).
METHODS: The analysis was performed on tumoral tissue and on corresponding normal tissue by using a panel of 37 polymorphic markers spanning 26 chromosomal regions.
RESULTS: We observed that only four chromosomal regions, 4q32 (30.00%), 4q35 (27.27%), 9q21-22 (28.57%), and 9q22-qter (35.71%), demonstrated a significative LOH (>20%), even if others show a borderline percentage (15-20%) of imbalance (1q32, 3p24, 10p22.1, and 17q21.3).
CONCLUSIONS: Our findings suggest that a new chromosomal region mapping in the long arm of chromosome 4 could be involved in sporadic BCC carcinogenesis. Further analyses indicate that the minimal deleted region in 4q32-35 includes p33ING2/ING1L and SAP30, whose deletion could impair the G1-phase checkpoint control and favor gene silencing, respectively.

Kataoka H, Bonnefin P, Vieyra D, et al.
ING1 represses transcription by direct DNA binding and through effects on p53.
Cancer Res. 2003; 63(18):5785-92 [PubMed] Related Publications
The ING family of proteins is involved in the regulation of diverse processes ranging from cell cycle and cellular senescence to apoptosis. These effects are most likely through activation of acetylation-dependent pathways that ultimately alter gene expression. Despite reports linking ING to p53 activation, the molecular basis of how ING activates p53 function has not been elucidated. In this study, we found that a subset of ING family members strongly repressed human alpha-fetoprotein (AFP) promoter activity but stimulated the p21(WAF1) promoter in parallel experiments in the same cell type, similar to the effects of p53. The p47(ING1a) isoform also repressed AFP promoter activity, but in contrast to other ING isoforms, it repressed the p21(WAF1) promoter. p47(ING3) up-regulated p21(WAF1) promoter activity, but it did not have any effect on the AFP promoter. ING1b and ING2 also repressed the AFP promoter in Hep3B p53-null cell lines, and p53 coexpression enhanced this transcriptional repression. Suppression of AFP gene transcription by ING was strongly dependent on AT-motifs that bind to the hepatocyte nuclear factor 1 (HNF1) transcription factor. Indeed, electrophoretic mobility shift assays confirmed that HNF1 binds to AT-motifs, but we found, surprisingly, that the ING1 complexes binding to these AT-motifs were devoid of HNF1 protein. Both ING1 and p53 were able to suppress AFP transcription and cause p21 induction; hSIR2, a negative regulator of the p53 protein, showed the opposite effects on the AFP promoter and, like HDAC1, repressed p21 promoter activity. In addition, we found that p33(ING1b) physically interacts with hSIR2, reverses its ability to induce the AFP promoter, and induces acetylation of p53 residues at Lys(373) and/or Lys(382). These findings provide novel evidence that p33(ING1b) represses AFP transcription by at least two mechanisms, one of which includes p53. The first is by binding to the AT-motif and excluding HNF1 binding while possibly targeting HAT activity to promoter regions, and the second is by increasing the levels of active, acetylated p53 via binding and inhibiting the ability of hSIR2 to deacetylate p53 protein.

Jäger D, Stockert E, Scanlan MJ, et al.
Cancer-testis antigens and ING1 tumor suppressor gene product are breast cancer antigens: characterization of tissue-specific ING1 transcripts and a homologue gene.
Cancer Res. 1999; 59(24):6197-204 [PubMed] Related Publications
SEREX (serological analysis of recombinant tumor cDNA expression libraries) has been applied to several different tumor types and has led to the identification of a wide range of tumor antigens. In this study, a breast cancer library and a normal testicular library were analyzed using autologous and allogeneic breast cancer sera. Thirty genes were isolated, including 27 known genes and 3 previously unknown genes. Among the known genes, two cancer-testis (CT) antigens, NY-ESO-1 and SSX2, previously defined by SEREX analysis, were found. In addition, ING1, a candidate breast cancer suppressor gene, was isolated. This ING1 gene product was also recognized by 2 of 14 allogeneic sera from breast cancer patients but not 12 normal adult sera. Comparison of ING1 cDNA from normal and tumor tissues showed no mutation in the index breast cancer case and revealed the presence of at least three different mRNA transcripts with variable transcription initiation sites and exon usage. Tissue-specific expression of these transcripts was found in normal tissues and tumor cell line mRNAs. Furthermore, a novel gene, designated as ING2, sharing 76% nucleotide homology with ING1 was identified in the breast cancer cDNA library. The basis of the immunogenicity of ING1 and the biological role of ING1 and ING2 need further exploration.

Shimada Y, Saito A, Suzuki M, et al.
Cloning of a novel gene (ING1L) homologous to ING1, a candidate tumor suppressor.
Cytogenet Cell Genet. 1998; 83(3-4):232-5 [PubMed] Related Publications
The ING1 gene encodes p33(ING1), a putative tumor suppressor for neuroblastomas and breast cancers, which has been shown to cooperate with p53 in controlling cell proliferation. We have isolated a novel human gene, ING1L, that potentially encodes a PHD-type zinc-finger protein highly homologous to p33(ING1). Fluorescence in situ hybridization and radiation-hybrid analyses assigned ING1L to human chromosome 4. Both ING1 and ING1L are expressed in a variety of human tissues, but we found ING1L expression to be significantly more pronounced in tumors from several colon-cancer patients than in normal colon tissues excised at the same surgical sites. Although the significance of this observation with respect to carcinogenesis remains to be established, the data suggest that ING1L might be involved in colon cancers through interference with signal(s) transmitted through p53 and p33(ING1).

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