Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Identification of a homozygous deletion in cancer cells provides strong evidence for the location of a tumor suppressor gene (TSG). We analyzed the 2p24 homozygous deletion of a non-small-cell lung cancer (NSCLC) cell line, NCI-H2882, and found that the deletion size was 3.7 Mbp. Since RhoB, which has been suggested to be a candidate TSG, was located in this region, we analyzed RhoB for alterations in NSCLC. Although we found no mutations in 48 cell lines including 20 NSCLCs, a loss of heterozygosity (LOH) analysis in 128 primary NSCLCs showed that 25 of 62 informative samples had LOH at the RhoB locus. Northern blot analysis of 28 cell lines (including 15 NSCLCs) indicated that RhoB expression was downregulated in 27. We analyzed RhoB expression in 112 primary NSCLCs with immunohistochemistry and found no or a weak RhoB expression in 33 (42%) of 78 adenocarcinomas, whereas we found it in 29 (94%) of 31 squamous cell carcinomas. No or a weak expression of RhoB was more frequently observed in poorly- or moderately-differentiated adenocarcinomas than in well-differentiated ones (p = 0.0014). Furthermore, no or a weak expression of RhoB indicated a tendency to poor patient prognosis. Although hypermethylation was not found at the promoter region, the RhoB expression in NSCLC cell lines was induced by histone deacetylase inhibition, suggesting that RhoB downregulation may be due to histone modification. The present study demonstrates that RhoB expression is frequently downregulated in NSCLCs by multiple mechanisms, suggesting that RhoB is a candidate TSG for NSCLC.
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PMID:RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line. 1709 27

CYP2A13, which is highly active in the metabolic activation of tobacco-specific nitrosamines, is selectively expressed in the respiratory tract, in which it is believed to play an important role in chemical carcinogenesis. The aim of this study was to determine the basis for tissue-specific regulation of CYP2A13 gene expression. We have shown that expression of CYP2A3, the rat homolog of CYP2A13, is regulated by nuclear factor I (NFI) in a tissue-specific manner. In the present study, we found that the transcriptional regulation of human CYP2A13 gene involves CCAAT/enhancer binding protein (C/EBP) transcription factors instead of NFI. DNase I footprinting and gel-shift assays with human lung nuclear extract identified two DNA elements bound by C/EBP. Reporter gene assays using a 216-base pair CYP2A13 promoter fragment confirmed the activation of CYP2A13 by transfected C/EBP factors, and results from chromatin immunoprecipitation assays indicated that C/EBP is associated with CYP2A13 promoter in vivo in the olfactory mucosa of CYP2A13-transgenic mice. In NCI-H441 human lung cancer cells, we discovered that CYP2A13 expression can be induced by a combined treatment with 5-aza-2'-deoxycytosine, a DNA demethylation agent, and trichostatin, a histone deacetylation inhibitor. In 5-aza-2'-deoxycytosine/trichostatin-treated NCI-H441 cells, overexpression of C/EBPdelta, a lung-enriched C/EBP, led to additional increases in CYP2A13 expression, whereas C/EBPdelta knockdown by small interference RNA suppressed CYP2A13 expression, findings that confirm a role for C/EBP in CYP2A13 regulation. Our findings pave the way for further studies of the regulation of the CYP2A13 gene, particularly the gene's potential suppression by airway inflammation, and the role of epigenetic modulation in the gene's tissue-selective expression.
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PMID:Transcriptional regulation of human CYP2A13 expression in the respiratory tract by CCAAT/enhancer binding protein and epigenetic modulation. 1714 54

Expression of cyclooxygenase-2 (COX-2) is associated with the pathogenesis of inflammation and various cancers, including lung cancer. Yin Yang 1 (YY1) is a zinc-finger transcription factor that interacts with histone acetyltransferases and deacetylases for its transcriptional activity and also is involved in inflammation and tumorigenesis. We investigated whether YY1 regulates COX-2 expression. We located a possible YY1 binding site proximal to the transcription initiation site of the COX-2 promoter. Electrophoretic mobility shift assays show that YY1 bound to the putative YY1 site in vitro. To show biological relevance, we performed chromatin immunoprecipitation assays showing that lipopolysaccharide (LPS) treatment induced YY1 binding to the cognate site in the endogenous COX-2 promoter. Overexpression of YY1 in macrophages treated with either LPS or live Pseudomonas aeruginosa increased COX-2 transcriptional activity. Furthermore, YY1 enhanced COX-2 protein expression and prostaglandin D(2) production elicited by LPS treatment. Mechanistically, we observed that LPS treatment resulted in disruption of an interaction between YY1 and p300, a histone acetyltransferase, but did not affect the interaction between YY1 and histone deacetylase 1/2. These data suggest that in response to LPS, YY1 dissociates from p300 and binds to the COX-2 promoter, contributing to COX-2 expression in an inflammatory milieu.
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PMID:Yin Yang 1 enhances cyclooxygenase-2 gene expression in macrophages. 1722 Mar 75

Despite considerable efforts to improve the diagnosis and treatment of lung cancer, this disease remains the leading cause of cancer-related mortality worldwide. Recent elucidation of epigenetic regulation of gene expression during malignant transformation, together with the identification of agents that modulate DNA methylation and histone acetylation, provide new opportunities for the treatment and prevention of lung cancer via chromatin remodeling mechanisms. Further analysis of molecular response in tumor tissues following exposure to chromatin remodeling agents may enable us to identify novel mechanisms pertaining to lung cancer epigenetics, and design more efficacious regimens.
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PMID:Targeting the epigenome for the treatment of thoracic malignancies. 1724 Aug 24

The use of 5-methylcytosine demethylating agents in conjunction with inhibitors of histone deacetylation may offer a new therapeutic strategy for lung cancer. Monitoring the efficacy of gene demethylating treatment directly within the tumour may be difficult due to tumour location. This study determined the positive and negative predictive values of sputum and serum for detecting gene methylation in primary lung cancer. A panel of eight genes was evaluated by comparing methylation detected in the primary tumour biopsy to serum and sputum obtained from 72 patients with Stage III lung cancer. The prevalence for methylation of the eight genes in sputum (21-43%) approximated to that seen in tumours, but was 0.7-4.3-fold greater than detected in serum. Sputum was superior to serum in classifying the methylation status of genes in the tumour biopsy. The positive predictive value of the top four genes (p16, DAPK, PAX5 beta, and GATA5) was 44-72% with a negative predictive value for these genes > or =70%. The highest specificity was seen for the p16 gene, and this was associated with a odds ratio of six for methylation in the tumour when this gene was methylated in sputum. In contrast, for serum, the individual sensitivity for all genes was 6-27%. Evaluating the combined effect of methylation of at least one of the four most significant genes in sputum increased the positive predictive value to 86%. These studies demonstrate that sputum can be used effectively as a surrogate for tumour tissue to predict the methylation status of advanced lung cancer where biopsy is not feasible.
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PMID:Predicting gene promoter methylation in non-small-cell lung cancer by evaluating sputum and serum. 1740 56

Epigenetic events, a key driving force in the development of lung cancer, two changes integral to epigenetic transcriptional control are DNA methylation and covalent modification of histone proteins. Aberrant methylation may be the most common mechanism of inactivating cancer-related genes in lung cancer, and histone modification may be closely associated with DNA methylation. It was seemed that epigenetic changes could be of the earliest events observed during cancer development, making them excellent targets for chemoprevention. Understanding the mechanisms involved in epigenetic regulation and how they interact with genetic changes during lung cancer progression could facilitate development of newer, more efficacious, and safer chemopreventive agents.
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PMID:[Research progress on epigenetics of lung cancer]. 1742 62

Advanced second generation inhibitors of histone deacetylases (HDAC) are currently used in clinical development. This study aimed at comparing the pharmacological properties of selected second generation HDAC inhibitors with the hydroxamate and benzamide head group, namely SAHA, LAQ824/LBH589, CI994, MS275 and MGCD0103. In biochemical assays using recombinant HDAC1, 3, 6 and 8 isoenzymes, SAHA and LAQ824/LBH589 behave as quite unselective HDAC inhibitors. In contrast, the benzamides CI994, MS275 and MGCD0103 are more selective, potent inhibitors of at least HDAC1 and HDAC3. All HDAC inhibitors induce histone H3 hyperacetylation, correlating with inhibition of proliferation, induction of cell differentiation and apoptosis. A broad cytotoxicity is seen across cell lines from different tumor entities with LAQ824/LBH589 being the most potent agents. The apoptosis inducing activity is evident in arrested and proliferating RKO colon cancer cells with inducible, heterologous p21(waf1) expression, indicative for a cell-cycle independent mode-of-action. Differentiation of MDA-MB468 breast cancer cells is induced by benzamide and hydroxamate analogs. The reversibility of drug action was evaluated by pulse treatment of A549 lung cancer cells. Whereas paclitaxel induced irreversible cell cycle alterations already after 6 hr treatment, HDAC inhibitor action was retarded and irreversible after >16 hr treatment. Interestingly, pulse treatment was equally effective as continous treatment. Finally, the efficacy of LAQ824, SAHA and MS275 in A549 nude mice xenografts was comparable to that of paclitaxel at well tolerated doses. We conclude that despite a different HDAC isoenzyme inhibition profile, hydroxamate and benzamide analogs as studied display similar cellular profiles.
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PMID:Distinct pharmacological properties of second generation HDAC inhibitors with the benzamide or hydroxamate head group. 1745 59

Evidence indicates that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of non-small-cell lung cancer (NSCLC). In addition to overproduction by COX-2, PGE2 concentrations also depend upon the levels of the PGE2 catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH). We find a dramatic down-regulation of PGDH protein in NSCLC cell lines and in resected human tumors when compared with matched normal lung. Affymetrix array analysis of 10 normal lung tissue samples and 49 resected lung tumors revealed a much lower expression of PGDH transcripts in all NSCLC histologic groups. In addition, treatment with the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) erlotinib increased the expression of 15-PGDH in a subset of NSCLC cell lines. This effect may be due in part to an inhibition of the extracellular signal-regulated kinase (ERK) pathway as treatment with mitogen-activated protein kinase kinase (MEK) inhibitor U0126 mimics the erlotinib results. We show by quantitative reverse transcription-PCR that the transcript levels of ZEB1 and Slug transcriptional repressors are dramatically reduced in a responsive cell line upon EGFR and MEK/ERK inhibition. In addition, the Slug protein, but not ZEB1, binds to the PGDH promoter and represses transcription. As these repressors function by recruiting histone deacetylases to promoters, it is likely that PGDH is repressed by an epigenetic mechanism involving histone deacetylation, resulting in increased PGE2 activity in tumors. This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI.
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PMID:Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer. 1757 21

Histone methyltransferase (HMT) enzymes that methylate the lysine of histones are involved in chromatin-mediated gene expression. Previously, we reported that a novel polymorphism of SUV39H2, the HMT that is required for the methylation of H3-K9, was associated with an increased risk of lung cancer in Koreans. The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is also a member of a histone/protein-methyltransferase superfamily, and the inactivation of RIZ in many cancers was detected as frameshift mutations, hypermethylation and missense mutations. In this study, we show the association of RIZ polymorphisms with the risk of lung cancer. In a hospital-based study of 335 lung cancer patients and 335 age- and gender-matched healthy controls, 120 polymorphisms of RIZ were screened. Of the 120 genotyped single nucleotide polymorphisms (SNPs), 42 SNPs were selected for the statistical analysis based on their frequency (>5%) and linkage disequilibrium [LD; only a representative SNP was analyzed if there were absolute LDs (r2 = 1)]; this resulted in three LD blocks. The +92337G>A and +95701C>A polymorphisms showed a statistically significant association with the reduced risk of lung adenocarcinomas after correcting the P values for multiple testing [for carrying one variant allele versus none, adjusted odds ratio (aOR) = 0.55 (95% CI = 0.38-0.78), corrected P = 0.04; aOR = 0.54 (95% CI = 0.38-0.77), corrected P = 0.02, respectively]. One haplotype (Ht5) in LD block 3 of RIZ was significantly associated with the reduced risk of lung adenocarcinomas (aOR = 0.28, 95% CI = 0.13-0.58) as well as overall lung cancer (aOR = 0.50, 95% CI = 0.30-0.82). This study suggested that RIZ polymorphisms may be important predictive markers for lung cancer susceptibility.
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PMID:Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer. 1769 62

To identify the tumor suppressor genes (TSG) associated with non-small cell lung cancers (NSCLC), we performed the loss of heterozygosity (LOH) analysis in NSCLC samples from 66 patients. We focused on the novel hot spot region on 15q14-24 with eight polymorphic microsatellite markers. Frequent allelic loss was detected in 33 of 48 informative cases (69%) at D15S984 on 15q23. We defined the fine map on the region and identified the SIN3A gene as a candidate TSG. The SIN3A gene product is a component of the histone deacetylase (HDAC) complex and plays essential roles in early embryonic development and the proliferation and survival of a variety of cells through the repression of diverse signaling pathways. Our expression analysis revealed more frequent down-regulation of the SIN3A mRNA in 19 of 31 cases (61%) of NSCLCs in comparison to those of other flanking genes (16-42%), albeit the correlation of the decreased expression with the LOH did not attain statistic significance. These results suggest that the attenuated function of SIN3A due to a decreased level of expression may result in epigenetic de-regulation of growth-related genes through histone acetylation, which leads to the tumorigenesis of lung cancer cells. To our knowledge, this is the first evidence of the down-regulation of the SIN3A gene in human cancer.
Lung Cancer 2008 Jan
PMID:Decreased expression of the SIN3A gene, a candidate tumor suppressor located at the prevalent allelic loss region 15q23 in non-small cell lung cancer. 1785 49


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