Journal
EPIGENETICS
Volume 5, Issue 5, Pages 402-409Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/epi.5.5.11853
Keywords
prostate cancer; superoxide dismutase 1; DNA methylation; oxidative stress; Sod1; Igf2; H19
Funding
- National Institutes of Health [R01CA97131, T32 AG000213-16]
- University of Wisconsin George M. O'Brien Urology Research Center [1P50DK065303]
- John Livesey endowment
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Increased oxidative stress and concordant DNA methylation changes are found during aging and in many malignant processes including prostate cancer. Increased oxidative stress has been shown to inhibit DNA methyltransferase in in vitro assays, but whether this occurs in vivo is unknown. To generate increased oxidative stress we utilized mice containing mutations in the CuZnSOD (Sod1) gene, a major superoxide dismutase in mammals. Increased 8-hydroxy-2'-deoxyguanosine, an adduct indicating oxidative damage, was found in liver and prostate tissues at 2 and 12 mo Sod1(+/-) mice compared to controls. Prostate tissues from Sod1+/- mice demonstrated decreased weight at 2 mo compared to controls, but this difference was not significant at 12 mo. Histologic changes were not seen. Global DNA methylation was significantly decreased at 2 mo in the prostate in Sod1+/- mice. 11p15 containing the epigenetically modulated insulin-like growth factor 2 (Igf2) and H19 genes, both which display oncogenic functions, may be particularly sensitive to oxidative stress. CpG island methylation at an intergenic CTCF binding site and the Igf2 P3 promoter was decreased in Sod1 mutants compared to controls. This is the first in vivo study to show that a deficiency of Sod1 leads to a decrease in DNA methylation. These studies indicate that increased oxidative stress, a factor implicated in neoplasia, can induce DNA hypomethylation in prostate tissues.
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