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Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer.

ABSTRACT: BACKGROUND: CpG hypermethylation in gene promoters is a frequent mechanism of tumor suppressor gene silencing in various types of cancers. It usually occurs at early steps of cancer progression and can be detected easily, giving rise to development of promising biomarkers for both detection and progression of cancer, including breast cancer. 5-aza-2'-deoxycytidine (AZA) is a DNA demethylating and anti-cancer agent resulting in induction of genes suppressed via DNA hypermethylation. RESULTS: Using microarray expression profiling of AZA- or DMSO-treated breast cancer and non-tumorigenic breast (NTB) cells, we identified for the first time TAGLN gene as a target of DNA hypermethylation in breast cancer. TAGLN expression was significantly and frequently downregulated via promoter DNA hypermethylation in breast cancer cells compared to NTB cells, and also in 13/21 (61.9 %) of breast tumors compared to matched normal tissues. Analyses of public microarray methylation data showed that TAGLN was also hypermethylated in 63.02 % of tumors compared to normal tissues; relapse-free survival of patients was worse with higher TAGLN methylation; and methylation levels could discriminate between tumors and healthy tissues with 83.14 % sensitivity and 100 % specificity. Additionally, qRT-PCR and immunohistochemistry experiments showed that TAGLN expression was significantly downregulated in two more independent sets of breast tumors compared to normal tissues and was lower in tumors with poor prognosis. Colony formation was increased in TAGLN silenced NTB cells, while decreased in overexpressing BC cells. CONCLUSIONS: TAGLN gene is frequently downregulated by DNA hypermethylation, and TAGLN promoter methylation profiles could serve as a future diagnostic biomarker, with possible clinical impact regarding the prognosis in breast cancer.

SUBMITTER: Sayar N

PROVIDER: S-EPMC4587865 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer.

Sayar Nilufer N Karahan Gurbet G Konu Ozlen O Bozkurt Betul B Bozdogan Onder O Yulug Isik G IG

Clinical epigenetics 20150928

<h4>Background</h4>CpG hypermethylation in gene promoters is a frequent mechanism of tumor suppressor gene silencing in various types of cancers. It usually occurs at early steps of cancer progression and can be detected easily, giving rise to development of promising biomarkers for both detection and progression of cancer, including breast cancer. 5-aza-2'-deoxycytidine (AZA) is a DNA demethylating and anti-cancer agent resulting in induction of genes suppressed via DNA hypermethylation.<h4>Res ...[more]

PMID: 26421063

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Project description:BackgroundSmad interacting protein-1 is a transcription factor that is implicated in transforming growth factor-?/bone morphogenetic protein signaling and a repressor of E-cadherin and human telomerase reverse transcriptase. It is also involved in epithelial-mesenchymal transition and tumorigenesis. However, genetic and epigenetic alterations of SIP1 have not been fully elucidated in cancers. In this study, we investigated mutations and promoter hypermethylation of the SIP1 gene in human hepatocellular carcinomas.MethodsSIP1 expression was analyzed in HCC cell lines and primary tumors in comparison to normal and non-tumor liver tissues by using semi-quantitative RT-PCR, quantitative real-time RT-PCR and immunohistochemistry. Mutation and deletion screening of the SIP1 gene were performed by direct sequencing in HCC-derived cells. Restoration of SIP1 expression was sought by treating HCC cell lines with the DNA methyl transferase inhibitor, 5-AzaC, and the histone deacetylase inhibitor, TSA. SIP1 promoter methylation was analyzed by the combined bisulfite restriction analysis assay in in silico-predicted putative promoter and CpG island regions.ResultsWe found that the expression of SIP1 was completely lost or reduced in five of 14 (36%) HCC cell lines and 17 of 23 (74%) primary HCC tumors. Immunohistochemical analysis confirmed that SIP1 mRNA downregulation was associated with decreased expression of the SIP1 protein in HCC tissues (82.8%). No somatic mutation was observed in SIP1 exons in any of the 14 HCC cell lines. Combined treatment with DNA methyl transferase and histone deacetylase inhibitors synergistically restored SIP1 expression in SIP1-negative cell lines. Analysis of three putative gene regulatory regions revealed tumor-specific methylation in more than half of the HCC cases.ConclusionsEpigenetic mechanisms contribute significantly to the downregulation of SIP1 expression in HCC. This finding adds a new level of complexity to the role of SIP1 in hepatocarcinogenesis.

Project description:BackgroundAn important mechanism that promoter methylation-mediated gene silencing for gene inactivation is identified in human tumorigenesis. Methylated genes have been found in breast cancer (BC) and beneficial biomarkers for early diagnosis. Prognostic assessment of breast cancer remain little known. Zinc finger protein 132 (ZNF132) is downregulated by promoter methylation in prostate cancer and esophageal squamous cell carcinoma. However, no study provides information on the status of ZNF132, analyzes diagnosis and prognostic significance of ZNF132 in BC.MethodsIn the present study, the expression of ZNF132 mRNA and protein level was determined based on the Cancer Genome Atlas (TCGA) RNA-Seq database and clinical samples analysis and multiple cancer cell lines verification. P rognostic significance of ZNF132 in BC was assessed using the Kaplan-Meier plotter. Molecular mechanisms exploration of ZNF132 in BC was performed using the multiple bioinformatic tools. Hypermethylated status of ZNF132 in BC cell lines was confirmed via Methylation specific polymerase chain reaction (MSP) analysis.ResultsThe expression of ZNF132 both the mRNA and protein levels was downregulated in BC tissues. These results were obtained based on TCGA database and clinical sample analysis. Survival analysis from the Kaplan-Meier plotter revealed that the lower level of ZNF132 was associated with a shorter Relapse Free Survival (RFS) time. Receiver operating characteristic curve (ROC) of 0.887 confirmed ZNF132 had powerful sensitivity and specificity to distinguish between BC and adjacent normal tissues. Bioinformatic analysis showed that 6% ((58/960)) alterations of ZNF132 were identified from cBioPortal. ZNF132 participated in multiple biological pathways based on the Gene Set Enrichment Analysis (GSEA) database including the regulation of cell cycle and glycolysis. Finally, MSP analysis demonstrated that ZNF132 was hypermethylated in a panel of breast cancer cell lines and 5-aza-2'-deoxycytidine (5-Aza-dC) treatment restored ZNF132 expression in partial cell lines.ConclusionsResults revealed that hypermethylation of ZNF132 contributed to its downregulated expression and could be identified as a new diagnostic and prognostic marker in BC.

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Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer.

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Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer.

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