ING Genes in NSCLC

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1		Elisabeth Taucher	+ 2875 word(s)	2875	2021-08-19 05:01:53	\|
2	format correct	Vivi Li	Meta information modification	2875	2021-08-23 05:50:00	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers11081118

Carcinogenic mutations allow cells to escape governing mechanisms that commonly inhibit uncontrolled cell proliferation and maintain tightly regulated homeostasis between cell death and survival. Members of the inhibition of growth (ING) family act as tumor suppressors, governing cell cycle, apoptosis and cellular senescence. The molecular mechanism of action of ING genes, as well as their anchor points in pathways commonly linked to malignant transformation of cells, have been studied with respect to a variety of cancer specimens.

Inhibition of growth ING lung cancer NSCLC

1. Introduction

In cells of healthy tissue, multiple mechanisms are necessary to control cell proliferation and maintain a balance between cell death and survival. Carcinogenic mutations in cancer genes allow cells to escape these governing mechanisms, permitting them to grow and proliferate indefinitely ^[1]. Within recent years, protein-coding and non-coding genes have been proposed as cancer drivers and tumor suppressors ^[2]^[3]. Tumor suppressor genes usually control growth-regulatory mechanisms, whilst genetic alterations affecting those tumor suppressor genes lead to metastatic spread ^[4]^[5]^[6]. Tumor protein p53 is one of the most frequently mutated tumor suppressors in human malignancies, however other genes exerting similar functions whose mutations also cause cellular control mechanisms to fail have recently been outlined: The inhibition of growth (ING) gene family is a powerful mediator of transcriptional regulation, regulation of the cell cycle, apoptosis, and cellular senescence ^[1]. All ING family members count among type II tumor suppressors since their inactivation leads to malignant transformation in different tissue types ^[7]^[8]. Until today, five human ING family genes (ING1–5) have been identified, with ING1 being the most widely studied. Initially, ING1 was isolated by means of subtractive hybridization between short segments of cDNAs ^[9]. The fragmented cDNAs were found to interfere with the activity of tumor suppressors by inhibiting protein synthesis through anti-sense sequences, or through truncated sense fragments that abrogate gene function in a dominant-negative fashion ^[9]. ING2, ING3, ING4, and ING5 were outlined by homology search. ING1 and ING2 form a distinct subgroup, as they have been found to be evolutionally and functionally close ^[10]. Characteristic for the ING proteins is a high homology in their C-terminal domain, containing a nuclear localization sequence and a plant homeodomain featuring a high affinity to histone 3 tri-methylated on lysine 4 (H3K4Me3) ^[10]. H3K4-methylation has been reported to act primarily as a repressor of protein-coding genes, and this repressive function is ever-decreasing with age ^[11]. The methylation pattern of H3K4 has been linked to carcinogenesis, and may even have diagnostic and/or prognostic significance in numerous types of cancers ^[12]. All ING family proteins are involved in the control of cell growth, senescence, apoptosis, chromatin remodeling, and DNA repair. In recent years, ING1 and ING2 have been described as tumor suppressor genes in various human cancer types, and both ING1 and ING2 knockout mice were found to spontaneously develop malignant diseases such as B cell lymphomas and soft tissue sarcomas ^[13]^[14]. The highly conserved c-terminal plant homeodomain that is characteristic for the ING family, and is generally found in chromatin remodeling proteins, as well as the nuclear localization sequence and the nuclear conserved region directing the genes to the nucleus, allows the ING genes to interact with chromatin and possibly nucleosomes ^[15]. The N-termini differ between the ING members and define their specific functions, for instance, their antagonistic regulatory properties ^[16]. Moreover, it has been demonstrated that ING gene family members also exert their various functions on the epigenetic level ^[17]. They act as histone mark sensors, core components of histone deacetylases (HDACs) 1 and 2, and histone acetyltransferase (HAT) chromatin-modifying complexes. Thereby INGs affect the hallmarks of cancer by altering gene methylation patterns, acting mainly as tumor suppressors ^[17].

2. ING1 and ING2 Act as Tumor Suppressors in Human Lung Cancer

In an in-depth analysis of lung cancer tissue samples and cell lines, Okano et al. sought to identify whether ING1 and ING2 are aberrantly expressed in human lung cancer ^[18]. By means of PCR-single strand conformation polymorphism (PCR-SSCP) and DNA sequence analysis, the ING2 gene was assessed. The expression of ING1b and ING2 was analyzed using quantitative real-time reverse transcription (RT)-PCR. Thirty-one primary lung cancer tissue samples were paired to matched controls. The samples consisted of 14 adenocarcinomas (AC), eight squamous cell carcinomas (SCC), six small cell lung cancers (SCLC), two large cell carcinomas and one adenosquamous cell carcinoma.

In addition, the authors investigated 15 human non-small cell lung cancer (NSCLC) cell lines as well as 15 human SCLC cell lines ^[19]. In the cell lines, PCR-SSCP analysis was carried out, and each of the exons of ING1b and ING2 was amplified by means of PCR primers. Afterward, DNA sequence analysis was performed ^[18]. The results of this analysis revealed aberrant expression patterns of ING1b and ING2 in six out of 31 lung cancer tissue samples, and in only one out of 30 lung cancer cell lines, i.e., in the NSCLC cell line NCI-H23. According to the DNA sequence analysis, the aberrant bands revealed a G to A substitution at codon 173, which does not lead to amino acid substitution. When matched with healthy control tissues, the same mutation was found in these as well, suggesting that it is due to gene polymorphism ^[18]. T to C substitution at codon 13 was detected in mutated bands in exon 1 of ING2, which occurred in 6 out of 31 lung cancer tissues. Moreover, this T to C substitution does not alter the amino acid encoded, and the authors conclude that also this aberration was due to polymorphism. In the cell lines, mRNA of ING1b and/or ING2 was up-regulated in seven out of eight lung cancer cell lines, as compared to the normal bronchial epithelium cell line BETA2A. Interestingly, all seven cell lines that exhibited up-regulation of ING1b mRNA also featured p53 mutations, while the remaining cell lines expressed wild-type p53 ^[18]. In seven out of eight lung cancer cell lines, ING2 mRNA was down-regulated, and among six of the seven cell lines that featured p53 mutation, reduced mRNA expression of ING2 was observed as well. Summing up these findings, ING1 and ING2 are evidently expressed differentially in human lung cancer, as compared to healthy lung tissue. Thus, these genes may serve as prognostic disease biomarkers for lung cancer in the future ^[18].

In immunohistochemical analysis, Zhao and colleagues analyzed expression profiles of the ING2 protein in normal versus cancer tissues ^[20]. Among the cancer specimens tested, there were 192 samples of human lung cancer. In addition, mouse tissues were analyzed for ING2 expression, comprising, among others, bronchial and alveolar tissue samples. Both tissue types were tested positive for cytoplasmic as well as nuclear ING2 protein expression. Interestingly, in human tissues, ING2 was universally expressed in the cytoplasm while only certain tissues featured nuclear ING2 expression as well ^[20]. According to this study, ING2 expression in lung cancer occurred infrequently, as compared to breast, ovarian, and endometrial cancer where the majority of cases expressed ING2.

ING1b has also been investigated with respect to NSCLC carcinogenesis. Therefore, tissue samples from 88 NSCLC patients who had undergone surgery were studied ^[21]. The samples comprised 35 ACs, 48 SCCs and five samples of large cell carcinoma. PCR-SSCP sequencing was performed for ING1 and the p53 gene mutation, as well as quantitative RT-PCR for ING1b, p21 and Bcl-2 associated X, apoptosis regulator (Bax) gene expression. For p21 and Bax protein expression, immunohistochemistry was performed. It was found that only two (2.3%) out of 88 NSCLC samples studied featured point mutations of the coding regions of ING1b. Standardized gene expression was determined by two pathologists who had no knowledge of the patients’ clinical data. In the 88 NSCLC samples studied, expression varied widely (0.768–0.404). In total, 37 carcinomas (42%) featured a diminished ING1b expression. No relation was found between ING1b expression and p53 gene status ^[21]. With respect to ING1b gene expression, the standardized p21 expression ratio tended to be higher in ING1b-positive tumors and was significantly lower in tumors that featured a reduced ING1b expression (p < 0.0029). Expression of the Bax gene also tended to be higher in ING1b-positive tumors and was significantly lower in tumor samples featuring a reduction in ING1b expression (p < 0.0001). The conclusion drawn from this analysis is an evident association of reduced ING1b gene expression with reduced p21 and Bax gene expression in NSCLC ^[21]. This study was the first study to show this correlation. ING1b thus has a tumor-suppressive function in NSCLC. The mode of action is obviously connected to the expression of p21 and Bax. However, the exact mechanism of this relationship still remains to be investigated in-depth.

In 2011, an interesting study was carried out by Luo and colleagues ^[22], investigating the role of ING1 in lung carcinoma. Two lung cancer cell lines were transfected with recombinant ING1b plasmids. One cell line, A549, expressed wild-type p53 whilst the other (SK-MES-1) featured p53 mutation. Apoptotic rate, alterations in the cell cycle, cell growth rate and downstream p21waf1 protein expression were assessed in both transfected cell lines. Additionally, the p33ING1b-p53 complex was analyzed by means of co-immunoprecipitation. For the detection of gene aberrations and the expression pattern of ING1, 70 cases of fresh-frozen lung carcinomas and 217 cases of formalin-fixed paraffin-embedded (FFPE) lung cancer samples were examined for loss of heterozygosity (LOH), p33ING1b protein expression by PCR-SSCP, as well as immunohistochemistry. As a result, over-expression of ING1b was found to inhibit cell growth of both A549 and SK-MES-1 cells, induced cell cycle arrest and apoptosis. The p21waf1 protein was significantly up-regulated, and a complex of p33ING1b and wtp53 could be detected after the wtp53 lung cancer cells had been transfected by ING1b. LOH correlated inversely with the expression of p33ING1b, and p33ING1b expression was lost in the majority (53%) of lung cancer specimens overall ^[22]. The authors conclude ING1 being a potent inhibitor of lung cancer cell growth, inducing cell cycle arrest and apoptosis by forming a complex with the wtp53 protein, and up-regulating p21waf1 ^[22].

p33ING1, p53 and the autophagy-related gene Beclin1 were investigated in NSCLC in another study from 2011, to find out more about the correlation between the expression of these genes with clinico-pathological parameters ^[23]. The researchers used NSCLC tissue gathered from operation, along with non-cancerous healthy lung tissue. mRNA, as well as protein expression of p33ING1, p53 and Beclin1, were detected by means of RT-PCR and Western blotting. mRNA and protein expression of p33ING1 and Beclin1 in NSCLC were significantly lower as compared to the surrounding healthy lung tissue (p < 0.05). Expression levels of p33ING1 mRNA and protein expression were found to be diminished in NSCLC specimens with good or middle differentiation, whilst they were higher in poorly differentiated NSCLC samples ^[23]. Conversely, the expression levels of p33ING1 and Beclin1 were lower in the presence of lymph node metastasis and higher with no lymph node metastases. Both markers were also expressed at higher levels in patients with stage I-II disease as compared to stage III-IV disease (p < 0.05). Interestingly, protein expression of mutated p53 in NSCLC was significantly higher in the lung cancer tissues than in the surrounding non-cancerous tissues ^[23]. On the basis of this data, it is not conclusive whether p33ING1 and Beclin1 act as tumor-suppressors or as tumor-promoters in NSCLC. Nevertheless, the combined detection of p33ING1, p53, and Beclin1 genes is suggested by the authors as a potential diagnostic tool for early diagnosis and estimation of prognosis in NSCLC ^[23].

Furthermore, ING1 has recently been investigated in the context of micro RNAs (miRNAs) by Jinag et al. ^[24]. MiRNAs have repeatedly been shown to be involved in NSCLC carcinogenesis, acting either as tumor promoters, or as tumor suppressors. In this study, miR-500 and miR-628 expression profiles were assessed by quantitative RT-PCR. Migration, invasion, proliferation, cell adhesion, and apoptotic rate were analyzed in order to gain knowledge about the function of these micro RNAs in NSCLC. Luciferase reporter assay was used to validate the direct targeting of ING1 by miR-500 as well as miR-628 ^[24]. In NSCLC tissues, miR-500 and miR-628 were expressed at higher levels in comparison to noncancerous tissues. Inhibition of miR-500 and miR-628 led to significant suppression of NSCLC cell proliferation, migration, invasion, and cell adhesion, and induced NSCLC cell apoptosis. In addition, it was shown that the ING1 gene was a direct target both for miR-500 and miR-628. ING1 over-expression inhibited NSCLC cell proliferation, migration, and invasion, and made cancer cells undergo apoptosis, according to this research study ^[24]. Conclusively, miR-500 and miR-628 act pro-carcinogenic in NSCLC, both targeting the tumor suppressor ING1.

An immunohistochemical study by Pan et al. was conducted in order to analyze the role of ING2 in lung carcinogenesis ^[25]. Sixty-four samples of NSCLC were tested for ING2 protein expression by means of immunohistochemistry, and the results were confirmed by Western blotting. Additionally, RT-PCR was used to evaluate ING2 mRNA levels as well. ING2 protein expression was found to be significantly decreased in this cohort of Chinese NSCLC patients ^[25], when compared to samples of normal lung tissue. ING2 was more frequently lost in AC (45.8%) than in SCC (26.3%). In the lung cancer samples, there was a shift of ING2 expression from the nucleus to the cytoplasm. Moreover, this study revealed a significant association between ING2 expression, lymph node metastasis, and TNM stage, albeit only for SCC and not for AC. According to this research study, ING2 is aberrantly expressed in NSCLC and is likely to contribute to lung carcinogenesis ^[25]. Down-regulation of ING2 protein expression was also confirmed by immunohistochemical analysis on 120 NSCLC specimens ^[26]. In >50% of the investigated samples, ING2 was down-regulated, which was more frequent in AC (68%) as compared to SCC (45%). No association with the patients’ gender, age, or five-years survival times were observed with respect to ING2. According to this study, no LOH or ING2 gene mutations were observed ^[26]. Notably, in 95% of the cancer samples examined, a silent single nucleotide polymorphism (SNP) was found. The authors of this study also investigated the promoter region of the ING2 gene, however, no alterations in the methylation pattern were identified. Conversely to previous reports, no correlation between p53 activity and ING2 expression levels was seen in this study ^[26]. As a conclusion, also this data suggests an impact of ING2 on NSCLC development.

Finally, it is also worth mentioning that ING2 is the major target of the HDAC inhibitor vorinostat ^[27], which was proven efficient also in the treatment of NSCLC patients ^[28]. Interestingly, ING1 protein phosphorylation status impacts the cross-talk of the p33(ING1b) splicing isoform of ING1 with members of the 14-3-3 protein family ^[29]. The 14-3-3 proteins are expressed in human tissues universally and have the ability to interact with diverse signaling pathways, altering protein expression, function of kinases, phosphatases, and transmembrane receptors. Further, 14-3-3 binding resulted in a significant transfer of p33(ING1b) protein to the cytoplasm ^[29]. Hence, it is likely that 14-3-3 influences the activity of p33(ING1b) significantly by directing its subcellular localization ^[29]. A novel function of ING2 was recently identified, i.e., the control of DNA replication and the maintenance of genome stability ^[30]. In small interfering RNA (siRNA) ING2 cells, global replication rate was significantly reduced during normal S-phase of the cell cycle, which was demonstrated by DNA fiber spreading experiment. In accordance with this finding, ING2 was also shown to interact with proliferating cell nuclear antigen, regulating its amount to the chromatin fraction, which allows for normal cell replication and cell proliferation. A high proportion of siRNA ING2 cells showed endo-reduplication of their genome and an increased ratio of sister chromatin exchange. The authors of this study thus propose that ING2 exerts its tumor-suppressive function by directly maintaining DNA integrity ^[30].

3. ING3 and Its Potential Role in Lung Cancer

To the best of our knowledge, no data on the impact of ING3 in lung cancer have been published yet. According to a review article from 2017, high expression levels of ING3 are found in healthy tissues that feature a rapid cell proliferation, such as the small intestine, bone marrow, or the epidermis ^[31]^[32]. It was also shown that ING3 is expressed to a significantly higher degree in proliferating versus quiescent epithelial cells. Contrary to pre-existing data on the other ING gene family members, data on ING3 suggests rather pro-carcinogenic effects of this particular gene, since high levels of ING3 correlate with more rapid cell growth. On the other hand, down-regulation of ING3 was observed in hepatocellular carcinoma and in colorectal adenocarcinoma ^[33]^[34]. In accordance with that, loss of ING3 was found to be associated with head and neck carcinogenesis ^[35]. ING3 induces germ cell apoptosis and embryonic death in a p53-dependent manner ^[36]. The link to tumor protein p53 has also been described for ING1b ^[21]. The function of the NuA4 histone acetyltransferase multi-subunit complex is linked p53 as well and is also mediated by ING3 ^[37]. NuA4 is essential for cell cycle proliferation and DNA-repair. Thus, ING3 is likely to impact cell proliferation by regulating NuA4. Similarly to ING4, interaction with p21 and Bax was demonstrated for ING3 as well: it was shown that ING3 induced the expression of p21 and Bax which resulted in apoptosis and diminished cell proliferation as shown in the RKO colon carcinoma cell line ^[38]. Data specifically on the role of ING3 in lung cancer is still very limited. Since previous research has shown controversial results, i.e., ING3 having anti-proliferative effects, whilst enhancing proliferation in other studies, it would be interesting to outline its mechanism of action in lung cancer in the future.

The ING3 protein was investigated in the context of cell cycle arrest, p53-transactivated promoters of p21 and Bcl2-associated X protein ^[39]. Immunohistochemistry was used to characterize ING3 expression profiles in tissue microarrays comprising various cancer specimens. Amongst these were 192 samples of lung cancer. Additionally, mouse tissue was analyzed, and ING3 cytoplasmic, as well as nuclear expression, was detected in the murine healthy bronchial and alveolar epithelial cells. Similar to ING2 ^[20], also ING3 was expressed in some lung cancer samples but occurred most abundantly in gynecological cancer entities. The authors conclude ING3 being involved in the repair and regeneration of tissues and point out a particular role in gynecological carcinogenesis ^[39].

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1. Introduction

2. ING1 and ING2 Act as Tumor Suppressors in Human Lung Cancer

3. ING3 and Its Potential Role in Lung Cancer

References