Unknown,Transcriptomics,Genomics,Proteomics

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Human melanoma cells over-express Extracellular Matrix 1 (ECM1) which is regulated in part by TFAP2C

ABSTRACT: Extracellular Matrix 1(ECM1) expression is increased in multiple tumor cell lines and primary cancers. Activator protein 2C (TFAP2C) is a potent regulator of ECM1 transcription. TFAP2C may contribute to the increased ECM1 expression noted in many cancers. This is the first report identifying the minimal promoter region of the human ECM1 gene and its regulation by TFAP2C Human A375 melanoma cells were assessed for mRNA and protein expression of ECM1. A mininal promoter region for ECM1 transactivation was identified. ECM1 expression was regulated in part by TFAP2C, and in ChIP-Seq experiments, TFAP2C was found to bind directly to the ECM1 gene in A375 melanoma cells and in MCF7 breast cancer cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas Bair

PROVIDER: E-GEOD-41234 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The complexity of gene regulation has created obstacles to defining mechanisms that establish the patterns of gene expression characteristic of the different clinical phenotypes of breast cancer. Transcription factor TFAP2C plays a critical role in the regulation of both estrogen receptor-alpha (ERM-NM-1) and c-ErbB2/HER2 (Her2). Herein, we performed chromatin immunoprecipitation and direct sequencing (ChIP-seq) for TFAP2C in four breast cancer cell lines representing different clinical phenotypes. Comparing the genomic binding sites for TFAP2C in the various cell lines, we identified that glutathione peroxidase (GPX1) is regulated by TFAP2C through an AP-2 regulatory region in the promoter of the GPX1 gene. Knock-down of TFAP2C, but not the related factor TFAP2A, resulted in an abrogation of GPX1 expression. Selenium-dependent GPX activity correlated with endogenous GPX1 expression, and overexpression of exogenous GPX1 induced GPX activity and significantly increased resistance to tert-butyl hydroperoxide. Methylation of the CpG island encompassing the AP-2 regulatory region was identified in cell lines where TFAP2C failed to bind the GPX1 promoter and GPX1 expression was unresponsive to TFAP2C. Furthermore, in cell lines where GPX1 promoter methylation was associated with gene silencing, treatment with 5-aza-dC (an inhibitor of DNA methylation) resulted in activation of GPX1 RNA and protein expression. Methylation of the GPX1 promoter was identified in approximately 20% of primary breast cancers and a highly significant correlation between TFAP2C and GPX1 expression was confirmed when considering only those tumors with an unmethylated promoter, whereas the related factor, TFAP2A, failed to demonstrate a correlation. The results demonstrate that TFAP2C regulates the expression of GPX1, which influences the redox state and sensitivity to oxidative stress induced by peroxides. Given the established role of GPX1 in breast cancer, the results provide an important mechanism for TFAP2C to further influence oncogenesis and progression of breast carcinoma cells. 4 ChIP-Seq data for TFAP2C in human breast carcinoma cell lines MCF-7, BT-474, MDA-MB-453 and SKBR-3.

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Human melanoma cells over-express Extracellular Matrix 1 (ECM1) which is regulated in part by TFAP2C

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