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Research Paper
Epigenetic Regulation of Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells
Michael Hitchler, Kornwipa Wikainapakul, Lei Yu, Kristy Powers, Watcharee Attatippaholkun and Frederick Domann
volume 1 | issue 4
october/november/ december 2006Pages: 163 - 171
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Malignant breast cancer cells often exhibit lower expression and activity of manganese superoxide dismutase (MnSOD) than their normal cell counterparts; however, the mechanism(s) responsible for this change remains unclear. We examined whether SOD2, the gene encoding MnSOD, was epigenetically repressed in breast cancer cell lines by DNA methylation and histone acetylation. RT-PCR analysis of SOD2 mRNA showed the non-tumorigenic breast epithelial cell line MCF-10A to have two to three fold higher expression levels than either UACC-893 or MDA-MB-435 breast carcinoma cells. Analysis of a region in the SOD2 promoter by sodium bisulfite genomic sequencing demonstrated significantly higher levels of CpG methylation in both human breast carcinoma cell lines assessed than in MCF-10A cells. CREB binding in vitro to a cognate site derived from this region was repressed by DNA methylation, and CREB binding to the 5’ regulatory region of the SOD2 gene in vivo as determined by ChIP was significantly lower in breast carcinoma cells than in MCF-10A. Increased cytosine methylation was also accompanied by a significant decrease in the level of acetylated histones in the same region of the SOD2 promoter. Finally, a causal link between cytosine methylation and transcriptional repression was established by increasing MnSOD mRNA, protein and activity in breast carcinoma cells using the DNA methyltransferase inhibitor 5-aza-2’-deoxycytidine. These findings indicate that epigenetic silencing of SOD2 constitutes one mechanism leading to the decreased expression of MnSOD observed in many breast cancers.
Authors
Michael Hitchler
University of Iowa, Iowa City, IA
Kornwipa Wikainapakul
Mahidol University, Bangkok, Thailand.
Lei Yu
University of Iowa, Iowa City, IA
Kristy Powers
University of Iowa, Iowa City, IA
Watcharee Attatippaholkun
Mahidol University, Bangkok, Thailand
Frederick Domann
University of Iowa, Iowa City, IA
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.