ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression

Abstract

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-jB binding site was found in the ING2 promoter region. We confirmed that NF-jB 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. Inhibitor of growth 2 (ING2), which is a member of ING gene family, was identified by searching EST databases for any similarity to the ING1 gene. A previous report has shown that the ING2 mRNA is expressed in testis at the highest level among normal tissues, and also emphasizes that ING2 mRNA expression is remarkably increased in colon cancer tissue compared to nonmalignant tissue.2 ING2 as well as ING1b are considered to be candidate tumor suppressor genes, which cooperate with p53 and share many biological functions, such as apoptosis, cell cycle regulation and senescence.3-7 Our recent report has shown that ING2 expression is suppressed by nutlin-3a-induced p53, resulting in the induction of senescence in normal human fibroblasts and a cancer cell line.8 ING family proteins functionally form complexes with several factors possessing intrinsic histone acetyltransferase (HAT) and histone deacetylase complex (HDAC) activities, thus, linking the function of ING genes to chromatin remodeling and transcriptional regulation through histone modifications.9-15 Among ING proteins, ING2 especially has a potential ability to bind to the trimethylated histone H3 at lysine 4 (H3K4me3). H3K4me3 correlates with transcriptional activation, while methylations occurred at many other histone residues are associated with transcriptional suppression. [16][17][18] Previous reports suggest that ING2 only induces gene expression and does not repress expression of any known genes in normal fibroblasts. 19ING2 also interacts with phosphatidylinositol 5-phosphate (PtdIns5P). 20,21 PtdIns5P, which may function in a nuclear signaling pathway, has been implicated as a critical regulator of nuclear signaling events during cell-cycle progression.22,23 Cellular stress, such as UV irradiation or oxidative stress, causes the accumulation of nuclear PtdIns5P, resulting in the activation of ING2. 24,25 Oxidative and nitrosative stress are linked with inflammation-associated cancer including colon carcinoma. 26 We report here evidence that pathophysiological expression of ING2 may enhance invasion and metastasis of colon cancer by increasing the expression of MMP13. Material and methods Clinical samples and RNA extractionFive colorectal...

Decreased expression of ING2 gene and its clinicopathological significance in Chinese NSCLC patients

“…Furthermore, in IHC results we investigated if the ING2 expression was translocated from nucleus to cytoplasm in several NSCLC tissues, especially in ING2 high staining samples, in contrast to normal tissues. In agreement with our results, the aberrantly localization of ING2 was also reported in some other tumors, including HCC [35] and colon cancer [22]. Moreover, study on ING1 and ING3, homologs of ING2, also found similar event in brain tumor [36] and HCC [37].…”

“…Another report by Saito M provides an animal model to study idiopathic and iatrogenic infertility in men found the function of ING2 in spermatogenesis and also demonstrated an evidence of ING2 as a tumor suppressor by increased incidence of soft-tissue sarcomas in Ing2-/-mice [33]. Interestingly, a research on colon cancer suggest ING2 also play roles as a tumor oncogene, which demonstrated ING2 was upregulated and increased invasion by enhanced MMP-13 [22]. In addition, a putative NF-κB binding site was found in the promoter of ING2 and the activation of NF-κB could positively regulate ING2 expression.…”

“…Most studies on ING1 addressed a significant decrease or loss of ING1 at mRNA and protein level, including lung cancer [21]. Although ING2 has been considered to be a candidate tumor suppressor gene for more than a decade, recent evidences suggest it also play roles as a tumor oncogene [22]. Since the complicated roles of ING2 played in various types of cancers, we investigated the expression of ING2 protein in Chinese NSCLC patients by immunohistochemistry and Western blotting, and then analyzed the associations between the protein expression status of ING2 and clinico-pathological features.…”

Role of ING Family Tumor Suppressors in Breast Cancer

“…Decrease of nuclear ING2 protein was observed in melanoma [57]. On the other hand increased expression of ING2 mRNA was shown in colon cancer [97]. We recently demonstrated that frequent deletion of ING2 locus at 4q35.1 associated with advanced tumor stage in HNSCC [98].…”

Role of ING Family Genes in Head and Neck Cancer and Their Possible Applications in Cancer Diagnosis and Treatment

“…Decrease of nuclear ING2 protein was observed in melanoma [50]. On the other hand increased expression of ING2 mRNA was shown in colon cancer [51]. Moreover, ING2 may play a role in melanoma initiation, since reduction of nuclear ING2 has been reported in radial as well as vertical growth phases in metastatic melanoma as compared to dysplastic nevi [52].…”