Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

DNA Methylation* ; Gene Expression Regulation, Neoplastic*; Breast Neoplasms/*genetics ; CpG Islands/*genetics ; Glutathione Peroxidase/*genetics ; Transcription Factor AP-2/*genetics; Azacitidine/analogs & derivatives ; Azacitidine/pharmacology ; Blotting, Western ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Chromatin Immunoprecipitation ; Decitabine ; Dose-Response Relationship, Drug ; Female ; Gene Expression Profiling ; Glutathione Peroxidase/metabolism ; Humans ; MCF-7 Cells ; Oligonucleotide Array Sequence Analysis ; Promoter Regions, Genetic/genetics ; Protein Binding/drug effects ; RNA Interference ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Transcription Factor AP-2/metabolism ; Transcription, Genetic ; tert-Butylhydroperoxide/pharmacology ; Glutathione Peroxidase GPX1

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. TFAP2C is a transcription factor that has a critical role in the regulation of both estrogen receptor-alpha (ERα) and c-ErbB2/HER2 (Her2). Herein, we performed chromatin immunoprecipitation and direct sequencing (ChIP-seq) for TFAP2C in four breast cancer cell lines. Comparing the genomic binding sites for TFAP2C, we identified that glutathione peroxidase (GPX1) is regulated by TFAP2C through an AP-2 regulatory region in the promoter of the GPX1 gene. Knockdown 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-2-deoxycytidine (5'-aza-dC) (an inhibitor of DNA methylation) allowed TFAP2C to bind to the GPX1 promoter resulting in the activation of GPX1 RNA and protein expression. Methylation of the GPX1 promoter was identified in ∼20% of primary breast cancers and a highly significant correlation between the 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.

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P30 ES005605 United States ES NIEHS NIH HHS; R01CA115438 United States CA NCI NIH HHS; R01 CA109294 United States CA NCI NIH HHS; R01CA109294 United States CA NCI NIH HHS; R01 CA115438 United States CA NCI NIH HHS; T32 CA078586 United States CA NCI NIH HHS; F30 AA019856 United States AA NIAAA NIH HHS; T32 GM007337 United States GM NIGMS NIH HHS; T32CA148062 United States CA NCI NIH HHS; T32 CA148062 United States CA NCI NIH HHS

GEO GSE36351

0 (TFAP2C protein, human)
0 (Transcription Factor AP-2)
776B62CQ27 (Decitabine)
955VYL842B (tert-Butylhydroperoxide)
EC 1.11.1.9 (Glutathione Peroxidase)
M801H13NRU (Azacitidine)
EC 1.11.1.9 (Glutathione Peroxidase GPX1)
EC 1.11.1.9 (GPX1 protein, human)

Date Created: 20120912 Date Completed: 20131126 Latest Revision: 20221207

20231215

PMC3522755

10.1038/onc.2012.400

22964634