Journal article
Transcriptional Regulation of the GPX1 Gene by TFAP2C and Aberrant CpG Methylation in Human Breast Cancer
Oncogene, Vol.32(34), pp.4043-4051
08/22/2013
DOI: 10.1038/onc.2012.400
PMCID: PMC3522755
PMID: 22964634
Abstract
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, which plays 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. 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) allowed TFAP2C to bind to the
GPX1
promoter resulting 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.
Details
- Title: Subtitle
- Transcriptional Regulation of the GPX1 Gene by TFAP2C and Aberrant CpG Methylation in Human Breast Cancer
- Creators
- Mikhail V Kulak - Department of Surgery, University of Iowa, Iowa City, IA 52242Anthony R Cyr - Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242George W Woodfield - Department of Surgery, University of Iowa, Iowa City, IA 52242Maria Bogachek - Department of Surgery, University of Iowa, Iowa City, IA 52242Philip M Spanheimer - Department of Surgery, University of Iowa, Iowa City, IA 52242Tiandao Li - Department of Biochemistry, University of Iowa, Iowa City, IA 52242David H Price - Department of Biochemistry, University of Iowa, Iowa City, IA 52242Frederick E Domann - Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242Ronald J Weigel - Department of Surgery, University of Iowa, Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.32(34), pp.4043-4051
- DOI
- 10.1038/onc.2012.400
- PMID
- 22964634
- PMCID
- PMC3522755
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Language
- English
- Date published
- 08/22/2013
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Surgery; Radiation Oncology; Biochemistry and Molecular Biology
- Record Identifier
- 9984024421202771
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