Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling by array of 5-Aza-2’-deoxycytidine treated gastric cancer cell lines

ABSTRACT: DNA methylation is a key contributor to normal mammalian development, although, abnormal CpG islands methylation has been described to have a role in carcinogenesis. In gastric cancer, it is observed a global hypomethylation within the bulk genome and local hypermethylation at specific tumor suppressor genes. Conversely, the absence of DNA methylation may be an important step in stable transcriptional activation of oncogenes, contributing to tumor development. The screening of genes modulated by DNA methylation in gastric cancer may contribute to the identification of tumor suppressor genes and/or oncogenes modulated by DNA methylation never described in this neoplasia. In this experiment we aimed to identify differentially expressed genes by comparing 5-Aza-2’-deoxycytidine (5-AZAdC)-treated and non-treated gastric cancer cell lines. 5-AZAdC is a demethylation agent and has received FDA approval for the treatment of myelodysplastic syndromes. This drug has also showed capacity to treat solid tumors with low dose. The ACP02 and ACP03 gastric cancer cell lines used in this experiment were previously established by our research group from primary gastric adenocarcinomas classified as diffuse and intestinal types, respectively. Both cell lines present chromosome 8 trisomy, MYC amplification, and TP53 loss of copy. Moreover, ACP03 is able to start a tumorigenesis process in Cebus apellas.

ORGANISM(S): Homo sapiens

SUBMITTER: Fernanda Wisnieski

PROVIDER: E-MTAB-7880 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. We sought to compare the differences in gene expression in vHMEC when compared to isogenic HMEC cells. Two time points in the vHMEC growth phase were used to assess if continual passage of vHMEC contributed to expression differences. RNA was extracted from a total of 4 HMEC (and matched vHMEC) lines.

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Transcription profiling by array of 5-Aza-2’-deoxycytidine treated gastric cancer cell lines

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