Dataset Information

Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation.

ABSTRACT: Disruption of signaling pathways that plays a role in the normal development and cellular homeostasis may lead to the dysregulation of cellular signaling and bring about the onset of different diseases, including cancer. In addition to genetic aberrations, DNA methylation also acts as an epigenetic modifier to drive the onset and progression of cancer by mediating the reversible transcription of related genes. Although the role of DNA methylation as an alternative driver of carcinogenesis has been well-established, the global effects of DNA methylation on oncogenic signaling pathways and the presentation of cancer is only emerging. In this article, we introduced a differential methylation parsing pipeline (MethylMine) which mined for epigenetic biomarkers based on feature selection. This pipeline was used to mine for biomarkers, which presented a substantial difference in methylation between the tumor and the matching normal tissue samples. Combined with the Data Integration Analysis for Biomarker discovery (DIABLO) framework for machine learning and multi-omic analysis, we revisited the TCGA DNA methylation and RNA-Seq datasets for breast, colorectal, lung, and prostate cancer, and identified differentially methylated genes within the NRF2-KEAP1/PI3K oncogenic pathway, which regulates the expression of cytoprotective genes, that serve as potential therapeutic targets to treat different cancers.

SUBMITTER: Lu J

PROVIDER: S-EPMC7692324 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation.

Lu Jennifer J Wilfred Premila P Korbie Darren D Trau Matt M

Cancers 20201030 11

Disruption of signaling pathways that plays a role in the normal development and cellular homeostasis may lead to the dysregulation of cellular signaling and bring about the onset of different diseases, including cancer. In addition to genetic aberrations, DNA methylation also acts as an epigenetic modifier to drive the onset and progression of cancer by mediating the reversible transcription of related genes. Although the role of DNA methylation as an alternative driver of carcinogenesis has be ...[more]

PMID: 33143142

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Project description:Estrogen signaling and epigenetic modifications, in particular DNA methylation, are involved in regulation of gene expression in breast cancers. Here we investigated a potential regulatory cross-talk between these two pathways by identifying their common target genes and exploring potential underlying molecular mechanisms in human MCF7 breast cancer cells. Principal Findings: Gene expression profiling revealed that the expression of approximately 150 genes was influenced by both 17β-estradiol (E2) and a hypomethylating agent 5-aza-2’-deoxycytidine (DAC). Based on gene ontology (GO), CpG island prediction analysis and previously reported estrogen receptor (ER) binding regions, we selected six genes for further analysis (BTG3, FHL2, PMAIP1, BTG2, CDKN1A and TGFB2). GO analysis suggests that these genes are involved in intracellular signaling cascades, regulation of cell proliferation and apoptosis, while CpG island prediction of promoter regions reveals that the promoters of these genes contain at least one CpG island. Using chromatin immunoprecipitation, we show that ERα is recruited to CpG islands in promoters, but neither in an E2- nor in a DAC-dependent fashion. DAC treatment reactivates the expression of all selected genes although only the promoters of BTG3 and FHL2 genes are methylated, with E2 treatment showing no effect on the methylation status of these promoters. Conclusions: We identified a set of genes regulated by both estrogen signaling and DNA methylation. However, our data does not support a direct molecular interplay of mediators of estrogen and epigenetic signaling at promoters of regulated genes. The aim of the study was to identify genes regulated by estrogen signaling and DNA methylation, using microarray approach. We compared the effects of E2 and DAC on global gene expression profiles in MCF7 cells. By comparing C_E2 (MP5-MP8 average) with C_EtOh samples (MP1-MP4 average), 802 genes were identified as up-regulated by E2, while 851 genes were identified as down-regulated by E2. 1017 genes were identified as up-regulated by DAC, by comparing A_EtOh (MP9-MP12 average) samples with C_EtOh, suggesting that DNA methylation is involved in their regulation. To identify possible common targets, we have compared the DAC up-regulated genes with E2-regulated genes. 88 annotated genes are found to be up-regulated by both E2 and DAC, suggesting that E2 has a hypomethylation-like effect on the regulation of these genes. 58 annotated genes are found to be down-regulated by E2 and up-regulated by DAC, suggesting that E2 has a hypermethylation-like effect on the regulation of these genes.

Dataset Information

Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation.

Publications

Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation.

Similar Datasets

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