Alteration of DNA methyltransferases contributes to 5′CpG methylation and poor prognosis in lung cancer

Lin, Ruo Kai; Hsu, Han Shui; Chang, Jui-Chi; Chen, Chih Yi; Chen, Jung Ta; Wang, Yi‐Ching

doi:10.1016/j.lungcan.2006.10.022

Cited by 212 publications

(173 citation statements)

References 32 publications

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“…The importance of both DNMT1 and DNMT3B expression in the maintenance of aberrant CpG island methylation of TSGs in mammalian cell models 20,[53][54][55] has been demonstrated. Our data together with previous reports [20][21][22] suggest that DNMT1 and DNMT3B can regulate DNA methylation in a promoter-specific manner. In concordance with this suggestion is the classification of common and distinct promoter groups identified after RNA interference-mediated suppression of DNMT1 and DNMT3B.…”

Section: Discussionsupporting

confidence: 87%

“…[17][18][19]21,47,48 A strong correlation between the expression levels of all the DNMTs was observed, in accordance with a reported coordinated expression of DNMTs. 22,47 Furthermore, the expression levels of all DNMTs examined in this set was correlated with the expression of E2F1. Although the E2F1 dependence of DNMT1 transcription is well established, 49 our data suggest that DNMT3A and DNMT3B may also be regulated by E2F1.…”

Section: Discussionmentioning

confidence: 81%

“…21,22 In addition, DNMT3B overexpression was correlated with hypermethylation of RASSF1 but not CDKN2A promoter. Interestingly, the same finding was reported for DDNMT3B in NSCLC.…”

Section: Discussionmentioning

confidence: 97%

“…15,16 Numerous studies have demonstrated frequent overexpression of the DNMTs in many cancer types, [17][18][19] which in some cases correlated with the hypermethylation of particular TSGs. [20][21][22] However, other reports suggest that DNMT overexpression does not by itself seem to sufficiently account for the hypermethylation of TSG promoters. 19,21,23,24 UHRF1 (also known as ICBP90) has recently been shown to play an important role in methylation maintenance.…”

mentioning

confidence: 98%

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UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Daskalos

Oleksiewicz

Filia

et al. 2010

Cancer

107

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BACKGROUND:The UHRF1 gene possesses an essential role in DNA methylation maintenance, but its contribution to tumor suppressor gene hypermethylation in primary human cancers currently remains unclear. METHODS: mRNA expression levels of UHRF1, DNMT1, DNMT3A, DNMT3B, and E2F1 were evaluated in 105 primary nonsmall cell lung carcinomas by quantitative polymerase chain reaction. The methylation status of CDKN2A and RASSF1 promoters was examined by pyrosequencing. UHRF1 was knocked down by short hairpin RNA in A549 lung adenocarcinoma cells. RESULTS: All 4 genes were overexpressed in a coordinated manner in the lung tumor tissues, and their expression correlated with that of E2F1. Higher UHRF1 expression in tumor tissues correlated with the hypermethylation of CDKN2A (P ¼ .005) and RASSF1 promoters (P ¼ .034), and the relationship with a combined epigenotype was even stronger (P ¼ 2.3 Â 10 À4 ). When UHRF1 was knocked down in A549 lung adenocarcinoma cells, lower methylation levels of RASSF1, CYGB, and CDH13 promoters were observed. Also, UHRF1 knockdown clones demonstrated reduced proliferation and decreased cell migration properties. CONCLUSIONS: Our data demonstrate that UHRF1 is a key epigenetic switch, which controls cell cycle in nonsmall cell lung carcinoma through its ability to sustain the transcriptional silencing of tumor suppressor genes by maintaining their promoters in a hypermethylated status. Thus, UHRF1 should be considered, along with DNMTs, among the potential targets for cancer treatment and/or therapeutic stratification.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 81%

“…21,22 In addition, DNMT3B overexpression was correlated with hypermethylation of RASSF1 but not CDKN2A promoter. Interestingly, the same finding was reported for DDNMT3B in NSCLC.…”

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 98%

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UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Daskalos

Oleksiewicz

Filia

et al. 2010

Cancer

107

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“…Previous studies have consistently reported that DNMT isoforms are significantly upregulated in human lung cancer cell lines and NSCLC tissue specimens (Sato et al, 2002;Vallbohmer et al, 2006). However, studies of the association between DNMT expression and clinical outcome in NSCLC patients have produced inconsistent results (Kim et al, 2006;Vallbohmer et al, 2006;Lin et al, 2007), and few have evaluated the prognostic value of MBD2. Therefore, we determined the expression of DNMT1, DNMT3b, and MBD2 by real-time quantitative PCR in 148 tumour samples from NSCLC patients and analysed their prognostic value, both separately and jointly.…”

mentioning

confidence: 99%

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

Xing

Stewart

et al. 2008

Br J Cancer

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The abnormality of DNA methylation is involved in tumour progression, and thus has a modulating effect on clinical outcome of cancer patients. In this study, we measured the mRNA expression levels of three methylation-regulating genes (DNMT1, DNMT3b, and MBD2) in 148 tumour samples from patients with non-small cell lung cancer (NSCLC) using quantitative real-time polymerase chain reaction and then determined their prognostic values. Our data showed that the high level of DNMT1 expression was significantly associated with an increased risk of death in all NSCLC patients (hazard ratio (HR), 1.74; 95% confidence interval (95% CI), 1.04 -2.90). However, the high level of DNMT3b expression was significantly associated with poor prognosis only in young patients (o65 years). The high level of MBD2 expression had a significantly reduced risk for death only in male patients and in squamous cell lung carcinoma (SQLC) patients. All three combination groups with DNMT1 and DNMT3b, DNMT1 and MBD2 or DNMT3b and MBD2 revealed significant combined effects in male patients and SQLC patients. Our results suggest that DNMT1, DNMT3b, and MBD2 may play important roles in modulating NSCLC patient survival and thus be useful for identifying NSCLC patients who would benefit most from aggressive therapy.

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DNA Methyltransferase Inhibitors

Sippl

Jung

2009

Epigenetic Targets in Drug Discovery

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The major two biochemical pathways of epigenetic regulation of transcription are DNA methylation and posttranslational modifications of amino acid side-chains in histones. The latter actually comprise a whole set of different biochemical modifications, such as reversible acetylation of lysines, methylation of arginines and lysines, phosphorylation, but also large molecule modifications such as sumoylation or ubiquitinylation. Those histone modifications interact with each other and constitute a pattern of alterations in the chromatin structure, the so-called histone code. Multiple enzymes are involved and the same modification on different amino acids in the histone proteins may lead to opposing effects of transcription [1]. The various modifications on histones and their biological consequences are outlined in other chapters in this book. DNA methylation refers to the enzymatic addition of a methyl group to nucleotide bases. There are three known types of base methylation: (i) adenine can be modified at the N-6 position (in bacteria, also in most eukaryotes) and cytosine can be modified (ii) at the N-4 position (mostly thermophilic bacteria) and (iii) at the C-5 position. The latter modification is the most common form of DNA alteration among all organisms [2]. Cytosine is methylated by DNA nucleotide methyltransferases (DNMTs) to 5-methylcytosine. The differences in biological significance of various patterns of methylation result from the stretch of DNA where the methylation takes place. Usually methylation of the promoter regions of genes results in repression of transcription. For DNMTs the first inhibitors are already approved for clinical use but there is much less work published that deals with novel inhibitors or structure-activity relationships [3], as compared to other epigenetic modulators, for example histone deacetylases. DNA MethylationDNMTs catalyze the methylation of cytosines located 5 0 to a guanosine as part of a CpG dinucleotide (CpG) in DNA to 5-methylcytosines using S-adenosyl methionine

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Alteration of DNA methyltransferases contributes to 5′CpG methylation and poor prognosis in lung cancer

Cited by 212 publications

References 32 publications

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

UHRF1‐mediated tumor suppressor gene inactivation in nonsmall cell lung cancer

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

DNA Methyltransferase Inhibitors

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