Epigenetic regulation and molecular characterization of C/EBPα in pancreatic cancer cells

Kumagai, Toru; Akagi, Tadayuki; Desmond, Julian C.; Kawamata, Norihiko; Gery, Sigal; Imai, Yasufumi; Song, Jee Hoon; Gui, Dorina; Said, Jonathan W.; Koeffler, H. Phillip

doi:10.1002/ijc.23994

Cited by 42 publications

(32 citation statements)

References 42 publications

(60 reference statements)

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“…At both the genetic and genomic levels, many hypermethylated genes previously reported in PC studies were identified as hypermethylated DMRs in the present study, including LHX1 , FOXE1 , PAX6 , BNIP3 [30], ALPP , CEBPA [31], CACNA1G [32], CCND2 [33], BAI1 , NRN1 , PENK , FAM84A , and ZNF415 [6]. In addition, our study identified other genes that are frequently hypermethylated in different types of cancer, such as RASSF1a , CDKN2A , hHML1 , and CDH1 [34,35].…”

Section: Discussionsupporting

confidence: 52%

High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq

et al. 2014

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BackgroundExtensive reprogramming and dysregulation of DNA methylation is an important characteristic of pancreatic cancer (PC). Our study aimed to characterize the genomic methylation patterns in various genomic contexts of PC. The methyl capture sequencing (methylCap-seq) method was used to map differently methylated regions (DMRs) in pooled samples from ten PC tissues and ten adjacent non-tumor (PN) tissues. A selection of DMRs was validated in an independent set of PC and PN samples using methylation-specific PCR (MSP), bisulfite sequencing PCR (BSP), and methylation sensitive restriction enzyme-based qPCR (MSRE-qPCR). The mRNA and expressed sequence tag (EST) expression of the corresponding genes was investigated using RT-qPCR.ResultsA total of 1,131 PC-specific and 727 PN-specific hypermethylated DMRs were identified in association with CpG islands (CGIs), including gene-associated CGIs and orphan CGIs; 2,955 PC-specific and 2,386 PN-specific hypermethylated DMRs were associated with gene promoters, including promoters containing or lacking CGIs. Moreover, 1,744 PC-specific and 1,488 PN-specific hypermethylated DMRs were found to be associated with CGIs or CGI shores. These results suggested that aberrant hypermethylation in PC typically occurs in regions surrounding the transcription start site (TSS). The BSP, MSP, MSRE-qPCR, and RT-qPCR data indicated that the aberrant DNA methylation in PC tissue and in PC cell lines was associated with gene (or corresponding EST) expression.ConclusionsOur study characterized the genome-wide DNA methylation patterns in PC and identified DMRs that were distributed among various genomic contexts that might influence the expression of corresponding genes or transcripts to promote PC. These DMRs might serve as diagnostic biomarkers or therapeutic targets for PC.

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Section: Discussionsupporting

confidence: 52%

High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq

et al. 2014

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“…C/EBPα requires localization in the nuclear region to exert its capacity for transcriptional activation and its biological function (19). Previous studies have demonstrated that C/EBPα is localized in the nucleus in normal epithelial cells; however, in cancer cells, C/EBPα is localized in the nucleus and cytoplasm (27). The present study also found that C/EBPα exhibited mixed nuclear and cytoplasmic localization in the bladder cancer cells.…”

Section: Discussionsupporting

confidence: 61%

Hypoxia regulates the expression and localization of CCAAT/enhancer binding protein α by hypoxia inducible factor-1α in bladder transitional carcinoma cells

Xue

Chen

2015

Molecular Medicine Reports

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Abstract. Hypoxia inducible factor-1α (HIF-1α) is overexpressed in various types of solid tumor in humans, including bladder cancer. HIF-1α regulates the expression of a series of genes, which are involved in cell proliferation, differentiation, apoptosis, angiogenesis, migration and invasion and represents a potential therapeutic target for the treatment of human cancer. Despite extensive investigation of the effects of HIF-1α in the progression and metastasis of bladder cancer, the possible regulatory mechanisms underlying the effects of HIF-1α on bladder cancer cell proliferation and differentiation remain to be elucidated. It has been suggested that the transcription factor CCAAT/enhancer binding protein α (C/EBPα) acts as a tumor suppressor in several types of cancer cell, which are involved in regulating cell differentiation, proliferation and apoptosis. The present study confirmed that, in bladder cancer cells, the expression and localization of C/EBPα was regulated by hypoxia through an HIF-1α-dependent mechanism, which may be significant in bladder cancer cell proliferation and differentiation. The 5637 and T24 bladder cancer cell lines were incubated under normoxic and hypoxic conditions. The expression levels of HIF-1α and C/EBPα were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence analysis. The results revealed that, under hypoxic conditions, the protein expression levels of HIF-1α were markedly upregulated, but the mRNA levels were not altered. However, the mRNA and protein levels of C/EBPα were significantly reduced. The present study further analyzed the subcellular localization of C/EBPα, which was markedly decreased in the nuclei under hypoxic conditions. Following HIF-1α small interference RNA silencing of HIF-1α, downregulation of C/EBPα was prevented in the bladder cancer cells cultured under hypoxic conditions. In addition, groups of cells treated with 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, which inhibits the expression of HIF-1α in hypoxia, contributed to the inhibited expression of HIF-1α and enhanced expression of C/EBPα in hypoxic bladder cancer cells. These results suggested that C/EBPα was a downstream effector regulated by HIF-1α in hypoxic bladder cancer cells and that this regulatory pathway may represent a potential therapeutic target in the treatment of bladder cancer.

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“…22). The cancer testis antigen GAGE4 was also derepressed as expected (23). We profiled gene expression levels after 5-aza-dC or mock treatment using microarrays, combining this with our methylation data to ascertain, in an unbiased manner, the proportion of methylated genes that were reactivated.…”

Section: Majority Of Genes Methylated In Breast Cancer Cell Lines Arementioning

confidence: 83%

Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer

Sproul

Nestor

Culley

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

138

127

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Aberrant promoter hypermethylation is frequently observed in cancer. The potential for this mechanism to contribute to tumor development depends on whether the genes affected are repressed because of their methylation. Many aberrantly methylated genes play important roles in development and are bivalently marked in ES cells, suggesting that their aberrant methylation may reflect developmental processes. We investigated this possibility by analyzing promoter methylation in 19 breast cancer cell lines and 47 primary breast tumors. In cell lines, we defined 120 genes that were significantly repressed in association with methylation (SRAM). These genes allowed the unsupervised segregation of cell lines into epithelial (EPCAM+ve) and mesenchymal (EPCAM−ve) lineages. However, the methylated genes were already repressed in normal cells of the same lineage, and >90% could not be derepressed by treatment with 5-aza-2′-deoxycytidine. The tumor suppressor genes APC and CDH1 were among those methylated in a lineage-specific fashion. As predicted by the epithelial nature of most breast tumors, SRAM genes that were methylated in epithelial cell lines were frequently aberrantly methylated in primary tumors, as were genes specifically repressed in normal epithelial cells. An SRAM gene expression signature also correctly identified the rare claudin-low and metaplastic tumors as having mesenchymal characteristics. Our findings implicate aberrant DNA methylation as a marker of cell lineage rather than tumor progression and suggest that, in most cases, it does not cause the repression with which it is associated.

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Epigenetic regulation and molecular characterization of C/EBPα in pancreatic cancer cells

Cited by 42 publications

References 42 publications

High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq

High-frequency aberrantly methylated targets in pancreatic adenocarcinoma identified via global DNA methylation analysis using methylCap-seq

Hypoxia regulates the expression and localization of CCAAT/enhancer binding protein α by hypoxia inducible factor-1α in bladder transitional carcinoma cells

Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer

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