Epigenetic regulation of the tumor suppressor gene
            <i>TCF21</i>
            on 6q23-q24 in lung and head and neck cancer

Smith, Laura T.; Lin, Mau-Ting; Brena, Romulo M.; Lang, James C.; Schuller, David E.; Otterson, Gregory A.; Morrison, Carl; Smiraglia, Dominic J.; Plass, Christoph

doi:10.1073/pnas.0510171102

Cited by 149 publications

(158 citation statements)

References 41 publications

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“…TCF21 is a class II basic helix-loop-helix transcription factor, which is expressed in the mesenchyme of developing organs, including lung, kidney and epicardium (15). TCF21 binds specific DNA sequences and negatively regulates various cell differentiation through modulating cell cycle arrest and tissue-specific gene expression (15), indicating that TCF21 has a role in the development of malignant tumors (16). Expression quantitative trait locus (eQTL) data and a reporter gene assay showed that the C allele of rs12190287 increased the expression of TCF21 in vascular smooth muscle cells (VSMCs) (2,17).…”

Section: Discussionmentioning

confidence: 99%

Association of a transcription factor 21 gene polymorphism with hypertension

Fujimaki

Oguri²,

Horibe

et al. 2014

Biomedical Reports

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Abstract.Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ 2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P<0.05) associated with hypertension. Allele frequencies for rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1) and genotype distributions for rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1) were also significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs12190287 of TCF21 (P=0.0014; recessive model; odds ratio, 1.21) was significantly associated with hypertension, and the C allele represented a risk factor for this condition. Similar analyses revealed that rs1122608 of SMARCA4 (P=0.0305; dominant model; odds ratio, 0.86), rs9369640 of PHACTR1 (P= 0.0119; dominant model; odds ratio, 0.82) and rs599839 of PSRC1 (P=0.0248; dominant model; odds ratio, 0.84) were also related to hypertension, with the minor T, C and G alleles, respectively, being protective against this condition. Thus, the present results indicate that rs12190287 (G→C) of TCF21 is a susceptibility locus for hypertension.

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Section: Discussionmentioning

confidence: 99%

Association of a transcription factor 21 gene polymorphism with hypertension

Fujimaki

Oguri²,

Horibe

et al. 2014

Biomedical Reports

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“…Malignant lesions are often defined by their differentiation status, where benign tumors and lowgrade cancers typically retain their epithelial phenotype and malignant cells acquire more fibroblastic mesenchymal phenotype (20). As mentioned in the results, Smith et al (11) previously reported highly significant induction of WNT4 expression in lung cancer cells (TCF21 expression negative) when transfected with TCF21. WNT4 has been associated previously with epithelialmesenchymal transition and epithelial phenotype (22).…”

Section: Discussionmentioning

confidence: 69%

“…Using restriction landmark genomic scanning, Smith et al (11) identified TCF21 as a candidate tumor suppressor at 6q23-q24 that is epigenetically inactivated in lung and head and neck cancers. In our article, using DNA sequencing, we examined lung cancer and bronchial epithelial cell lines for methylation of the CpG island within exon 1 of the TCF21 gene (GenBank accession no.…”

Section: Introductionmentioning

confidence: 99%

Differential Methylation of a Short CpG-Rich Sequence within Exon 1 of TCF21 Gene: A Promising Cancer Biomarker Assay

Shivapurkar

Stastny

Xie

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Detection of cancer cells at early stages could potentially increase survival rates in cancer patients. Aberrant promoter hypermethylation is a major mechanism for silencing tumor suppressor genes in many kinds of human cancers. A recent report from our laboratory described the use of quantitative methylation-specific PCR assays for discriminating patients with lung cancer from those without lung cancer using lung biopsies as well as sputum samples. TCF21 is known to be essential for differentiation of epithelial cells adjacent to mesenchyme. Using restriction landmark genomic scanning, a recent study identified TCF21 as candidate tumor suppressor at 6q23-q24 that is epigenetically inactivated in lung and head and neck cancers. Using DNA sequencing technique, we narrowed down a short CpG-rich segment (eight specific CpG sites in the CpG island within exon 1) of the TCF21 gene, which was unmethylated in normal lung epithelial cells but predominantly methylated in lung cancer cell lines. We specifically targeted this short CpG-rich sequence and developed a quantitative methylationspecific PCR assay suitable for high-throughput analysis. We showed the usefulness of this assay in discriminating patients with lung cancer from those without lung cancer using biopsies and sputum samples. We further showed similar applications with multiple other malignancies. Our assay might have important implications in early detection and surveillance of multiple malignancies. (Cancer Epidemiol Biomarkers Prev 2008;17(4):995 -1000)

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“…Among these 67 epigenetically induced or suppressed genes, some genes were previously reported to be related with lung cancer. TCF21, which regulates the mesenchymal cell transition into epithelial cells, has been demonstrated previously to be silenced in most head and neck squamous cell carcinomas and non-small-cell lung cancer tumor cells (Smith et al, 2006). SOSTDC1 has been reported previously to regulate the Wnt receptor signaling pathway, while Wnt has been implicated in skin cancer, lung cancer, bladder cancer, and leukemia, and may be oncogenic in other cancers (Reya and Clevers, 2005;Barker and Clevers, 2006;Polakis, 2007).…”

Section: Discussionmentioning

confidence: 99%

Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

Qh¹,

Xh²,

Zm³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Identification of epigenetic alterations in tumors has become a common method for identifying genes critical to cancer development and progression. Thus, we identified DNA methylation alterations on the genome scale during lung adenocarcinoma (LADC) progression to understand the carcinogenic process and identify clinically relevant biomarkers. We found that epigenetic alterations in LADC mainly occur during the early stage of LADC progression, and there are no significant methylation differences between early-stage and late-stage LADCs. This suggests that DNA methylation alterations characterize a turning point of early events in LADC progression. By comparing DNA methylation between early-stage LADCs and normal lung tissues, we further identified 940 genes with significant alterations in DNA methylation. Sixty-seven genes were found to exhibit strong correlation between methylation alterations and expression changes, based on associated gene expression data. According to gene ontology analysis, these genes are involved in lung development, respiratory 9200-9214 (2015) system development, cell cycle, histidine metabolism, the Wnt signaling pathway, and the p53 signaling pathway. We also found that genes on chromosome 18 most frequently showed promoter hypermethylation. Moreover, we found that LADC-associated DNA hypomethylation occurred preferentially at neither histone H3 lysine 4 nor histone H3 lysine 27 mark domains in human embryonic stem cells (NMDs) and that hypomethylation of NMDs was associated with a poor prognostic signature in LADC. Our findings have important implications for LADC progression because of the identification of novel epigenetic biomarkers potentially involved in early-stage LADC and for establishing the importance of NMD DNA hypomethylation for predicting prognosis in LADC.

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Epigenetic regulation of the tumor suppressor gene TCF21 on 6q23-q24 in lung and head and neck cancer

Cited by 149 publications

References 41 publications

Association of a transcription factor 21 gene polymorphism with hypertension

Association of a transcription factor 21 gene polymorphism with hypertension

Differential Methylation of a Short CpG-Rich Sequence within Exon 1 of TCF21 Gene: A Promising Cancer Biomarker Assay

Genome-scale meta-analysis of DNA methylation during progression of lung adenocarcinoma

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