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5-Aza-2'-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating Sipa1 promoter-proximal elements.

ABSTRACT: Human breast cancer cells exhibit considerable diversity in the methylation status of genomic DNA CpGs that regulate metastatic transcriptome networks. In this study, we identified human Sipa1 promoter-proximal elements that contained a CpG island and demonstrated that the methylation status of the CpG island was inversely correlated with SIPA1 protein expression in cancer cells. 5-Aza-2'-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, promoted the expression of Sipa1 in the MCF7 breast cancer cells with a low level of SIPA1 expression. On the contrary, in MDA-MB-231 breast cancer cells with high SIPA1 expression levels, hypermethylation of the CpG island negatively regulated the transcription of Sipa1 In addition, the epithelial-mesenchymal transition (EMT) was reversed after knocking down Sipa1 in MDA-MB-231 cells. However, the EMT was promoted in MCF7 cells with over-expression of SIPA1 or treated with 5-Aza-CdR. Taken together, hypomethylation of the CpG island in Sipa1 promoter-proximal elements could enhance SIPA1 expression in breast cancer cells, which could facilitate EMT of cancer cells, possibly increasing a risk of cancer cell metastasis in individuals treated with 5-Aza-CdR.

SUBMITTER: Lu A

PROVIDER: S-EPMC7240297 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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5-Aza-2'-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating Sipa1 promoter-proximal elements.

Lu Ang A Wang Wei W Wang-Renault Shu-Fang SF Ring Brian Z BZ Tanaka Yoshimasa Y Weng Jun J Su Li L

Journal of cell science 20200511 9

Human breast cancer cells exhibit considerable diversity in the methylation status of genomic DNA CpGs that regulate metastatic transcriptome networks. In this study, we identified human Sipa1 promoter-proximal elements that contained a CpG island and demonstrated that the methylation status of the CpG island was inversely correlated with SIPA1 protein expression in cancer cells. 5-Aza-2'-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, promoted the expression of Sipa1 ...[more]

PMID: 32193333

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Project description:BACKGROUND: DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. Aberrant epigenetic gene silencing in tumours is a frequent event, yet the factors which dictate which genes are targeted for inactivation are unknown. DNA methylation and histone acetylation can be modified with the chemical agents 5-aza-2'-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) respectively. The aim of this study was to analyse de-methylation and re-methylation and its affect on gene expression in colorectal cancer cell lines treated with 5-aza-dC alone and in combination with TSA. We also sought to identify methylation patterns associated with long term reactivation of previously silenced genes. METHOD: Colorectal cancer cell lines were treated with 5-aza-dC, with and without TSA, to analyse global methylation decreases by High Performance Liquid Chromatography (HPLC). Re-methylation was observed with removal of drug treatments. Expression arrays identified silenced genes with differing patterns of expression after treatment, such as short term reactivation or long term reactivation. Sodium bisulfite sequencing was performed on the CpG island associated with these genes and expression was verified with real time PCR. RESULTS: Treatment with 5-aza-dC was found to affect genomic methylation and to a lesser extent gene specific methylation. Reactivated genes which remained expressed 10 days post 5-aza-dC treatment featured hypomethylated CpG sites adjacent to the transcription start site (TSS). In contrast, genes with uniformly hypermethylated CpG islands were only temporarily reactivated. CONCLUSION: These results imply that 5-aza-dC induces strong de-methylation of the genome and initiates reactivation of transcriptionally inactive genes, but this does not require gene associated CpG island de-methylation to occur. In addition, for three of our selected genes, hypomethylation at the TSS of an epigenetically silenced gene is associated with the long term reversion of gene expression level brought about by alterations in the epigenetic status following 5-aza-dC treatment.

Dataset Information

5-Aza-2'-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating Sipa1 promoter-proximal elements.

Publications

5-Aza-2'-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating <i>Sipa1</i> promoter-proximal elements.

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