title: Superoxide dismutase 1 knockdown induces oxidative stress and DNA methylation loss in the prostate.
abstract: 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.
authors.affiliation: Department of Urology and University of Wisconsin Carbone Comprehensive Cancer Center, Madison, USA.
authors.forename: Sachin S
authors.initials: SS
authors.lastname: Bhusari
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Dobosy
authors.forename: Vivian
authors.initials: V
authors.lastname: Fu
authors.forename: Nima
authors.initials: N
authors.lastname: Almassi
authors.forename: Terry
authors.initials: T
authors.lastname: Oberley
authors.forename: David F
authors.initials: DF
authors.lastname: Jarrard
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D018899:CpG Islands; D004249:DNA Damage; D019175:DNA Methylation; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D044127:Epigenesis, Genetic; D018392:Genomic Imprinting; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics*; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D007335:Insulin-Like Growth Factor II; D000080242:8-Hydroxy-2'-Deoxyguanosine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003849:Deoxyguanosine
references.citation: Mutat Res. 2004 Apr 14;548(1-2):53-9
references.pmid: 15063136
references.citation: J Nutr. 2003 Nov;133(11 Suppl 1):3740S-3747S
references.pmid: 14608108
references.citation: Cancer. 2000 Jul 1;89(1):123-34
references.pmid: 10897009
references.citation: Ageing Res Rev. 2009 Oct;8(4):268-76
references.pmid: 19716530
references.citation: Science. 2003 Apr 18;300(5618):489-92
references.pmid: 12702876
references.citation: J Urol. 2007 Mar;177(3):822-31
references.pmid: 17296351
references.citation: Methods. 2000 Oct;22(2):135-47
references.pmid: 11020328
references.citation: Mutagenesis. 2007 Mar;22(2):91-103
references.pmid: 17284773
references.citation: Hum Mol Genet. 2006 Mar 1;15(5):705-16
references.pmid: 16421170
references.citation: J Biol Chem. 1969 Nov 25;244(22):6049-55
references.pmid: 5389100
references.citation: Hum Reprod. 1992 Jan;7(1):81-5
references.pmid: 1551966
references.citation: Anal Biochem. 1971 Nov;44(1):276-87
references.pmid: 4943714
references.citation: Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1261-4
references.pmid: 8108398
references.citation: Exp Physiol. 1997 Mar;82(2):291-5
references.pmid: 9129943
references.citation: Cancer Res. 1998 Sep 15;58(18):4023-37
references.pmid: 9751603
references.citation: Mutat Res. 2008 Apr 2;640(1-2):170-3
references.pmid: 18281064
references.citation: Science. 2006 Apr 14;312(5771):269-72
references.pmid: 16614224
references.citation: J Androl. 2002 May-Jun;23(3):341-51
references.pmid: 12002436
references.citation: Ann N Y Acad Sci. 1999;893:95-112
references.pmid: 10672232
references.citation: Nutrition. 2004 Jan;20(1):63-8
references.pmid: 14698016
references.citation: J Assist Reprod Genet. 2009 Sep-Oct;26(9-10):537-44
references.pmid: 19876730
references.citation: Prostate. 2006 Jan 1;66(1):57-69
references.pmid: 16114064
references.citation: Arch Biochem Biophys. 1997 Aug 15;344(2):424-32
references.pmid: 9264557
references.citation: Oncogene. 2005 Jan 13;24(3):367-80
references.pmid: 15531919
references.citation: Mutat Res. 1997 Apr 14;375(1):1-8
references.pmid: 9129674
references.citation: Cancer Res. 1991 Jun 15;51(12):3075-9
references.pmid: 2039987
references.citation: Nucleic Acids Res. 2004 Aug 09;32(14):4100-8
references.pmid: 15302911
references.citation: Cancer Lett. 2008 Jul 18;266(1):6-11
references.pmid: 18372104
references.citation: Science. 1994 Feb 25;263(5150):1128-30
references.pmid: 8108730
references.citation: Free Radic Biol Med. 2006 Jun 1;40(11):1993-2004
references.pmid: 16716900
references.citation: J Biol Chem. 1973 Jul 10;248(13):4793-6
references.pmid: 4578091
references.citation: Mol Cell Biol. 2003 Aug;23(15):5293-300
references.pmid: 12861015
references.citation: Carcinogenesis. 1995 May;16(5):1253-5
references.pmid: 7767994
references.citation: Urology. 2006 Dec;68(6):1145-51
references.pmid: 17169635
references.citation: Cancer Res. 2004 Mar 15;64(6):1975-86
references.pmid: 15026333
references.citation: Biochem Biophys Res Commun. 1996 May 15;222(2):362-7
references.pmid: 8670210
references.citation: Nature. 1991 Jan 31;349(6308):431-4
references.pmid: 1992344
references.citation: Free Radic Biol Med. 2007 Jul 15;43(2):202-15
references.pmid: 17603930
references.citation: Cancer Res. 2005 Aug 1;65(15):6773-9
references.pmid: 16061659
references.citation: Mol Endocrinol. 1997 Dec;11(13):1891-8
references.pmid: 9415394
references.citation: Prostate. 2000 Jul 1;44(2):144-55
references.pmid: 10881024
references.citation: Methods Mol Biol. 2006;314:183-99
references.pmid: 16673882
references.citation: Hear Res. 1982 Feb;6(2):141-51
references.pmid: 7061348
references.citation: Am J Pathol. 1999 Dec;155(6):1985-92
references.pmid: 10595928
references.citation: Am J Pathol. 2002 Feb;160(2):403-8
references.pmid: 11839558
references.citation: Free Radic Res. 1995 Sep;23(3):255-8
references.pmid: 7581820
references.citation: Methods Mol Biol. 2002;197:159-76
references.pmid: 12013794
references.citation: Prostate. 2008 Aug 1;68(11):1187-95
references.pmid: 18459101
references.citation: Prostate. 1989;15(3):263-71
references.pmid: 2479940
references.citation: Nat Rev Endocrinol. 2009 Jul;5(7):401-8
references.pmid: 19488075
references.citation: Biol Reprod. 2004 Jun;70(6):1790-7
references.pmid: 14960483
references.citation: Cancer Res. 2001 Aug 15;61(16):6025-8
references.pmid: 11507046
references.citation: Cancer Metastasis Rev. 1998-1999;17(4):325-30
references.pmid: 10453275