Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcriptome profiling of human pancreatic cancer cell line Panc1, MiaPaCa2, AsPC1 transfected with NFATc1-siRNA against siRNA of scrambled sequence

ABSTRACT: Genome-wide studies on pancreatic adenocarcinoma (PDAC) have indicated that numerous genes involved in carcinogenesis are highly methylated in their promoter regions but nevertheless strongly transcribed. It has been proposed that transcription factors may specifically bind to methylated promoters and up-regulate transcription. Screening a protein microarray presenting 658 transcription factors, we found that molecules of the NFAT (Nuclear Factor of Activated T-Cells) family preferentially bound to methylated promoter sequences. One family member – NFATc1 – was also strongly expressed in PDAC compared to control samples. To further identify targets of NFATc1 and study involved pathways, we have used siRNA to knockdown NFATc1 in three pancreatic cancer cell lines (Panc1, MiaPaCa2, AsPC1) with the help of the illumina beadchip arrays and we compared the transcriptional profiles of the cell lines under different knockdown conditions. We identify ALDH1A3 as direct targets of NFATc1, that NFATc1 binds the methylated promoter of ALDH1A3 and accelerate PDAC progression.

ORGANISM(S): Homo sapiens

SUBMITTER: Yenan Wu

PROVIDER: E-MTAB-10122 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Promoter Hypermethylation Promotes the Binding of Transcription Factor NFATc1, Triggering Oncogenic Gene Activation in Pancreatic Cancer.

Wu Yenan Y Kröller Lea L Miao Beiping B Boekhoff Henning H Bauer Andrea S AS Büchler Markus W MW Hackert Thilo T Giese Nathalia A NA Taipale Jussi J Hoheisel Jörg D JD

Cancers 20210911 18

Studies have indicated that some genes involved in carcinogenesis are highly methylated in their promoter regions but nevertheless strongly transcribed. It has been proposed that transcription factors could bind specifically to methylated promoters and trigger transcription. We looked at this rather comprehensively for pancreatic ductal adenocarcinoma (PDAC) and studied some cases in more detail. Some 2% of regulated genes in PDAC exhibited higher transcription coupled to promoter hypermethylati ...[more]

PMID: 34572796

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Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here we determine the contribution of epigenetically silenced genes to the development of PDAC. METHODS: We investigated methylated DNAs from PDACs, chronic pancreatitis and normal pancreatic tissues using Methyl-CpG immunoprecipitation followed by microarray hybridization. Promoter methylation of selected genes was confirmed with the Epityper assay. Expression levels were evaluated by quantitative RT-PCR. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanINs), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. RESULTS: A total of 3.8% of 27.800 interrogated CpG islands were hypermethylated in PDAC versus normal and chronic pancreatitis tissues. Hypermethylation was confirmed in 12 out of 13 selected islands and was associated with gene silencing in 4 of them. The most prominently hypermethylated gene, WNK2, was further investigated. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in pancreatic tumor cells than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expression were lower in PDAC and chronic pancreatitis compared to normal tissues both in patients and mouse models. Overexpression of WNK2 led to a reduced cell growth and WNK2 expression in tissues correlated negatively with the expression of pERK1/2, a downstream target of WNK2 responsible for cell proliferation. CONCLUSIONS: WNK2 is downregulated by promoter hypermethylation early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. 3 types of pancreatic tissue samples: 5 normals, 2 chronic pancreatitis, 7 tumors (PDAC)

Dataset Information

Transcriptome profiling of human pancreatic cancer cell line Panc1, MiaPaCa2, AsPC1 transfected with NFATc1-siRNA against siRNA of scrambled sequence

Publications

Promoter Hypermethylation Promotes the Binding of Transcription Factor NFATc1, Triggering Oncogenic Gene Activation in Pancreatic Cancer.

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