UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we isolated a candidate tumor-suppressor gene, MYO18B, which was inactivated in approximately 50% of human lung cancers by deletion, mutation, and promoter methylation. However, more frequent reduction or loss of MYO18B expression and restoration of MYO18B expression by trichostatin A (TSA) treatment suggested the contribution of other mechanisms, especially histone deacetylation, for epigenetic inactivation of the MYO18B gene. In this study, we examined histone modification of the promoter region of the MYO18B gene in 8 human lung cancer cell lines by a chromatin immunoprecipitation assay. In 6 of 7 cell lines with reduced or silenced MYO18B expression, the levels of histones H3 and H4 acetylation surrounding the MYO18B promoter region were lower than those in a cell line with MYO18B expression. By treatment with TSA, the levels of histone H3 and H4 acetylation were increased in all 6 cell lines whose MYO18B expression was restored by TSA, whereas neither H3 nor H4 acetylation was increased in cells whose MYO18B expression was not restored by TSA. Significant correlations were observed between the levels of histone H3/H4 acetylation and MYO18B expression. These results suggest that acetylation of both histones H3 and H4 contributes to regulation of MYO18B expression in lung cancer cells and that histone deacetylation surrounding the promoter region plays an important role in MYO18B silencing and is involved in lung carcinogenesis.
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PMID:Correlation between histone acetylation and expression of the MYO18B gene in human lung cancer cells. 1510 Oct 48

The SMARCA4/BRG1 gene product is a component of the SWI-SNF chromatin-remodeling complex and regulates gene expression by disrupting histone-DNA contacts in an ATP-dependent manner. Inactivating mutations of the SMARCA4 gene, on chromosome arm 19p, are present in several human cancer cell lines, including cell lines derived from lung cancers. Interestingly, loss of heterozygosity (LOH) at 19p and absence of the SMARCA4 protein have been reported in lung tumors. To evaluate further the possible contribution of SMARCA4 gene inactivation to lung carcinogenesis, we performed a complete analysis of the SMARCA4 gene to search for (a) point mutations in all 35 coding exons, including an existing splicing variant and the intron-exon boundaries, and (b) abrogation of gene expression through promoter hypermethylation by using the methylation-specific polymerase chain reaction (MSP) assay. We selected genomic DNA from 20 lung primary tumors with LOH on 19p for the screening of point mutations and 10 lung cancer cell lines and 52 lung primary tumors for the MSP analysis. Through our mutational screening, we identified an in-frame and germ-line insertion of 24 bp in exon 4 whose biological relevance is unknown. This variant was not detected in the germ line of the 62 additional individuals analyzed, indicating it is not a common polymorphism. Moreover, two missense alterations were identified in the tumors of 2 patients, a somatic Gly1160Arg mutation and a Ser1176Cys mutation. Neither was present in the germ line of the 51 additional lung cancer individuals tested. Because these mutations lead to substitution of highly conserved amino acids, they may affect the ATPase function of the protein. Finally, no promoter hypermethylation was observed in any lung primary tumor or cancer cell line, indicating that this is not a major mechanism for SMARCA4 inactivation during lung carcinogenesis. In conclusion, our data revealed that somatic point mutations of the SMARCA4 gene are present in a small subset of lung tumors, although mutations affecting the ATPase domain may be a hot-spot for SMARCA4 gene inactivation. We cannot rule out that other mechanisms, such as complete or partial deletions of the SMARCA4 gene, are contributing to the loss of the SMARCA4 protein in lung cancer.
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PMID:Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors. 1528 30

BRG1, also called SMARCA4, is the catalytic subunit of the SWI/SNF chromatin-remodelling complex and influences transcriptional regulation by disrupting histone-DNA contacts in an ATP-dependent manner. BRG1 and other members of the SWI/SNF complex become inactivated in tumours, implying a role in cancer development. To understand the contribution of BRG1 to lung tumourigenesis, we restored BRG1 in H1299 lung cancer cells and used cDNA microarray analysis to identify changes in gene expression. Forty-three transcripts became activated, whereas two were repressed. Chromatin immunoprecipitation of resulting candidate genes revealed that the CYP3A4 and ZNF185 promoters recruited BRG1 and that recruitment to the CYP3A4 promoter was specific to this gene and did not involve the CYP3A5 or CYP3A7 family members. Moreover, specifically BRG1 but not its homologue BRM was recruited to the CYP3A4 and ZNF185 promoters. To explore their potential relevance in lung tumours, levels of CYP3A4 and ZNF185 transcripts were evaluated in seven additional lung cancer cell lines. CYP3A4 was undetectable in any of the lung cancer cells tested, and only the CYP3A5 family member was present in the A549 and Calu-3 cells. In contrast, the amount of ZNF185 transcript clearly varied among lung cancer cell lines and severely reduced levels were observed in BRG1-deficient cells, except those of A427. We extended these observations to 27 lung primary tumours using real-time RT-PCR (TaqMan) and observed that four (15%) and 14 (52%) of them had BRG1 and ZNF185 downregulation, respectively, when compared with normal lung. No significant correlation between reduced levels of BRG1 and ZNF185 was observed, indicating that additional mechanisms to BRG1 inactivation may contribute to the loss of ZNF185 expression in lung tumours. In conclusion, our results provide evidence that transcriptional activation of ZNF185 and CYP3A4 is mediated by direct association of BRG1 with their promoters and also indicate that a decreased level of ZNF185 is a common feature of lung tumours and may be of biological relevance in lung carcinogenesis.
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PMID:Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells. 1573 Nov 17

The prognosis of lung cancer is very much limited by the difficulties of diagnosing early stage disease amenable to surgery. Thus, novel diagnostic and therapeutic approaches are urgently needed for this common type of cancer. Recently, epigenetic alterations of tumor cells have been defined for a multitude of tissues and genes. Thus, promoter hypermethylation of tumor suppressor genes, and other targets of neoplasia-associated methylation disturbances, have become the most frequent recurrent alteration in solid tumors and hematologic neoplasia. In lung cancer, several sets of genes including the tumor suppressor gene p16, the DNA repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), E-cadherin and retinoic acid receptor beta have been shown to be frequently methylated and inactivated. Distinct methylation patterns can provide molecular distinctions between different histologic subtypes of lung cancer. Gene hypermethylation in lung cancer is an early event associated with exposure to tobacco-specific carcinogens. Highly sensitive detection of hypermethylated DNA in sputum and peripheral blood offers a powerful tool for detecting lung cancer at an early stage. Epigenetic alterations in cancer, as opposed to genetic lesions, are potentially reversible. Thus, hypermethylation has been studied as a therapeutic target for agents which revert this epigenotype. The most advanced drugs to inhibit methylation are two azanucleosides, decitabine and its ribonucleoside analogue 5-azacytidine. In vitro, demethylating agents given at low doses reactivate tumor suppressor genes, and in mouse models, the development of lung cancer can be retarded. This effect is more powerful when histone acetylation, as a second epigenetic silencing mechanism, is also inhibited pharmacologically (HDAC inhibitors). Clinical trials of both groups of agents have been performed, and novel demethylating agents which are not incorporated into DNA offer further perspectives for epigenetic therapy of lung cancer and other malignancies.
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PMID:DNA methylation disturbances as novel therapeutic target in lung cancer: preclinical and clinical results. 1588 7

It has been documented that estrogen receptor (ER) transcription silencing due to hypermethylation is linked to the tumor progression of breast, uterine and prostate cancers. Additionally, ER hypermethylation in lung tumors has been associated with the exposure of specific carcinogens in animal study. The role of hypermethylation-induced ER transcription silencing in lung tumor progression and its prognostic value for non-small cell lung cancer (NSCLC) patients remained unclear. In our study, ER hypermethylation of 123 lung tumors and adjacent normal parts were examined by methylation-specific PCR (MSP). Estrogen receptor mRNA expression in lung tumors was determined by RT-PCR. Our data indicated that ER hypermethylation was only detected in lung tumors, but not in adjacent normal lung tissues. This suggests that ER hypermethylation may be associated with lung tumorigenesis. Among the clinical parameters studied, only gender factor was correlated with ER hypermethylation with a higher frequency of ER hypermethylation being in male patients than in female patients (58 vs. 34%, p = 0.01). After being stratified by gender and cigarette smoking status, a similarly high prevalence of ER hypermethylation was found in male smoking and nonsmoking patients (60 vs. 61%) as compared to that of female nonsmoking patients (34%). To investigate if 17-beta estradiol (E2) was responsible for such gender difference in ER hypermethylation, a lung cancer A549 cell with ER hypermethylation and without ER mRNA expression was treated with E2 of various concentrations for defined time intervals to show that an E2 treatment could restore the expression of ER mRNA and eliminate ER hypermethylation. Western blot data also showed that acetylated histone 3 and histone 4 of chromatin were increased significantly by E2 treatment. Thus, E2 can make ER mRNA re-expression by eliminating ER hypermethylation. To elucidate the prognostic value of ER hypermethylation, Kaplan-Meier analysis was carried out to show that patients with ER hypermethylation had a poorer prognosis than those without ER hypermethylation. Such prognostic prediction, however, applied only to male (p = 0.0044) patients. Cox regression analysis further showed the feasibility of ER hypermethylation as an independent prognostic factor of NSCLC (p = 0.007). It is possible that antiestrogens may have different therapeutic values for male and female lung cancer patients.
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PMID:Gender difference in estrogen receptor alpha promoter hypermethylation and its prognostic value in non-small cell lung cancer. 1598 39

We previously reported silencing of the TGF-beta type II receptor gene (TGFbetaRII), involving histone deacetylation, instead of DNA methylation (DNA-Me). Because different histone modifications may play crucial roles in the epigenetic alterations, we further studied links with silencing of the TGFbetaRII gene promoter in six lung cancer cell lines. ChIP assays demonstrated three chromatin patterns for this gene silencing (Pattern I: histone H3 acetylation (H3-Ac)(+/-)/histone H3 lysine 4 methylation (H3K4-Me)(+)/DNA-Me(-), Pattern II; H3-Ac(-)/H3K4-Me(+/-)/DNA-Me(-), and Pattern III; H3-Ac(-)/H3K4-Me(-)/DNA-Me(+)), indicating possible progressive alterations with H3K4-Me alteration. With exposure to a histone deacetylase inhibitor (HDAC-I), trichostatin A, cell lines with the pattern II demonstrated strong and persistent induction of TGFbetaRII expression, while those with the pattern III showed only weak or no induction. ACC-LC-91 cell line, one of the pattern II examples demonstrated strong and continuous induction of H3K4-Me similar to TGFbetaRII expression. In contrast, ACC-LC-176 with the pattern III showed only weak and transient induction of H3K4-Me, similar to TGFbetaRII expression. Treatment with 5-aza-2'-deoxycytidine (5aza-dC) in addition to HDAC-I resulted in strong and continuous induction of TGFbetaRII expression and H3K4-Me in ACC-LC-176, although 5aza-dC alone was without such effects. In ACC-LC-91, both H3-Ac and H3K4-Me were promptly and simultaneously induced by HDAC-I, and similarly inhibited by wortmannin, a PI3K family inhibitor, together with TGFbetaRII induction. These findings suggested progressive alterations of chromatin configuration including H3K4-Me alteration in TGFbetaRII gene silencing. A possible involvement of a wortmannin-sensitive kinase in histone modification was also suggested.
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PMID:Histone modification in the TGFbetaRII gene promoter and its significance for responsiveness to HDAC inhibitor in lung cancer cell lines. 1616 7

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.
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PMID:Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. 1617 Mar 53

The regulation of telomerase expression in normal cells is poorly understood. Moreover, the molecular mechanism underlying tumor-specific expression of telomerase remains unclear. We investigated the link between histone deacetylation and telomerase activity in normal lung and lung tumor cells. Four non-small-cell lung cancer (NSCLC) lines and one normal lung fibroblast line were tested for telomerase activity with or without Trichostatin A(TSA). The telomerase activity and the expression of telomerase associated components were determined by TRAP assay, RT-PCR analysis and Western blot analysis. All 4 NSCLC cell lines exposed to 1 microM TSA for 24 h had no change in telomerase activity or hTERT mRNA level. Telomerase activity was very low in normal lung fibroblasts (mrc-9) until exposed to 1 microM TSA for 24 h, at which time telomerase activity was readily detectable, with concomitant upregulation of hTERT mRNA (10-fold). The level of other telomerase associated components (hTER and TP1) were unaltered. Furthermore, 1 microM TSA exposure for 24 h did not alter the level of c-Myc or p21 mRNA. Immunodetection reveled that hTERT protein expression increased (approximately 6 fold) compared to c-Myc, p21, or gelsolin. The effect of TSA on hTERT expression is independent of DNA methylation as judged by 5-azacytidine (5aza) treatment. TSA effect on mrc-9 cells is unaltered even in the presence of 200 microg/ml cyclohexamide, suggesting a direct inhibition of histone deacetylation. Collectively, our study indicates that inhibition of histone deacetylation selectively regulates the transcriptional derepression of telomerase catalytic subunit in normal lung fibroblast cells compared to lung tumor cells.
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PMID:Histone deacetylation is directly involved in desilencing the expression of the catalytic subunit of telomerase in normal lung fibroblast. 1620 13

Alterations in chromatin structure resulting from aberrant DNA methylation and perturbations of the histone code profoundly influence gene expression during pulmonary carcinogenesis. Recent studies indicate that DNA demethylating agents and histone deacetylase (HDAC) inhibitors synergistically induce gene expression and apoptosis in cultured lung cancer cells, and prevent lung cancer development in animals following exposure to tobacco carcinogens. Preliminary clinical trials have established proof of principle regarding the use of DNA demethylating agents and HDAC inhibitors for enhancing immunogenicity and apoptosis of lung cancer cells, and have revealed the complexities concerning the mechanisms by which chromatin remodeling agents mediate antitumor effects in vivo. These data support additional investigations pertaining to the epigenetics of lung cancer, and the evaluation of chromatin remodeling agents for the treatment and prevention of this disease.
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PMID:Targeting the epigenome for the treatment and prevention of lung cancer. 1621 90

More effective therapies are needed for non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Proteasome inhibitors are one class of molecularly targeted antineoplastic agents being investigated for these diseases. These agents block the activity of the 26S proteasome, which is responsible for the degradation of the vast majority of intracellular proteins and thus affect multiple signaling pathways within cells. Bortezomib is the first proteasome inhibitor to be evaluated in human studies and is approved for use in multiple myeloma. Bortezomib is now being investigated as a potential treatment for NSCLC and SCLC. Preclinical studies have shown that single-agent bortezomib causes growth inhibition and apoptosis in numerous NSCLC cell lines in vitro and has antitumor activity in vivo. Bortezomib affects the levels of several proteins known to be of significance in lung cancers. Studies of bortezomib in combination with other antitumor agents in vitro and in vivo demonstrate that these combination regimens can offer additive/synergistic effects compared with the single agents. Bortezomib has been investigated in combination with taxanes, gemcitabine, carboplatin, histone deactylase inhibitors, and other molecularly targeted agents in various NSCLC cell lines. The sequence of administration of the agents in preclinical combination regimens in vitro and in vivo has been shown to be of significance; further elucidation of the mechanism of efficacy of bortezomib in lung cancer is required. Numerous clinical studies have been carried out or are ongoing. Bortezomib has the potential to play a significant role in the future management of NSCLC and SCLC.
Clin Lung Cancer 2005 Oct
PMID:Preclinical data with bortezomib in lung cancer. 1625 Sep 27

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