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Clin Cancer Res. 2009 Jun 1;15(11):3672-9. doi: 10.1158/1078-0432.CCR-08-2343. Epub 2009 May 19.

Interaction of TFAP2C with the estrogen receptor-alpha promoter is controlled by chromatin structure.

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  • 1Departments of Surgery, Radiation Oncology, and Biochemistry, University of Iowa, Iowa City, Iowa, USA.

Abstract

PURPOSE:

Transcriptional regulation of estrogen receptor-alpha (ERalpha) involves both epigenetic mechanisms and trans-active factors, such as TFAP2C, which induces ERalpha transcription through an AP-2 regulatory region in the ERalpha promoter. Attempts to induce endogenous ERalpha expression in ERalpha-negative breast carcinomas by forced overexpression of TFAP2C have not been successful. We hypothesize that epigenetic chromatin structure alters the activity of TFAP2C at the ERalpha promoter.

EXPERIMENTAL DESIGN:

DNA methylation, histone acetylation, and chromatin accessibility were examined at the ERalpha promoter in a panel of breast carcinoma cell lines. TFAP2C and polymerase II binding were analyzed by chromatin immunoprecipitation. Epigenetic chromatin structure was altered using drug treatment with 5-aza-2'-deoxycytidine (AZA) and trichostatin A (TSA).

RESULTS:

The ERalpha promoter in the ERalpha-negative lines MDA-MB-231, MCF10A, and MCF7-5C show CpG island methylation, histone 3 lysine 9 deacetylation, and decreased chromatin accessibility compared with ERalpha-positive cell lines MCF7 and T47-D. Treatment with AZA/TSA increased chromatin accessibility at the ERalpha promoter and allowed TFAP2C to induce ERalpha expression in ERalpha-negative cells. Chromatin immunoprecipitation analysis showed that binding of TFAP2C to the ERalpha promoter is blocked in ERalpha-negative cells but that treatment with AZA/TSA enabled TFAP2C and polymerase II binding.

CONCLUSION:

We conclude that the activity of TFAP2C at specific target genes depends upon epigenetic chromatin structure. Furthermore, the combination of increasing chromatin accessibility and inducing TFAP2C provides a more robust activation of the ERalpha gene in ERalpha-negative breast cancer cells.

PMID:
19458056
[PubMed - indexed for MEDLINE]
PMCID:
PMC2776721
Free PMC Article
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