title: GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD.
abstract: Glutamate carboxypeptidase II (GCPII) haplotypes were found to influence susceptibility to prostate cancer. In the current study, we have elucidated the impact of these haplotypes on the expression of PSMA, BNIP3, Ec-SOD, GSTP1 and RASSF1 genes to understand the epigenetic basis of oxidative stress and prostate cancer risk. Expression analysis was carried out by RT-PCR. Bisulphite treated DNA was subjected to MS-PCR and COBRA for epigenetic studies. Plasma MDA and glutathione levels were measured. In prostate cancer, upregulation of BNIP3 (204.4 ± 23.77 vs. 143.9 ± 16.42 %, p = 0.03); and downregulation of Ec-SOD (105.8 ± 13.69 vs. 176.3 ± 21.1 %, p = 0.027) and RASSF1A (16.67 ± 16.0 vs. 90.8 ± 8.5 %, p = 0.0048) was observed. Hypomethylation of BNIP3 (31.25 ± 16.19 vs. 45.70 ± 2.42 %, p < 0.0001), hypermethylation of Ec-SOD (71.4 ± 6.75 vs. 10.0 ± 3.78 %, p < 0.0001) and RASSF1 (76.25 ± 12.53 vs. 30.0 ± 8.82 %, p = 0.0077) was observed in prostate cancer. The gene expression signature of PSMA, BNIP3, Ec-SOD, GSTP1, clearly demarcated cases and controls (AUC = 0.89 in the ROC curve). D191V variant of GCPII showed positive association with oxidative stress and inverse association with Ec-SOD expression. H475Y variant showed positive association with Ec-SOD expression and inverse association with oxidative stress. R190W variant was found to reduce oxidative stress by increasing glutathione levels. GCPII genetic variants contribute to increased oxidative stress and prostate cancer risk by modulating the CpG island methylation of Ec-SOD.
authors: Departments of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Panjagutta, Hyderabad, 500082, India.
authors: Shree
authors: S
authors: Divyya
authors: Shaik Mohammad
authors: SM
authors: Naushad
authors: P V L N
authors: PV
authors: Murthy
authors: Ch Ram
authors: ChR
authors: Reddy
authors: Vijay Kumar
authors: VK
authors: Kutala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000954:Antigens, Surface / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D005978:Glutathione / Q000097:blood; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000235:genetics; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012372:ROC Curve; D013482:Superoxide Dismutase / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000954:Antigens, Surface; C090121:BNIP3 protein, human; D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D009573:Nitrites; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D008315:Malondialdehyde; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D005978:Glutathione
references: Gut. 2006 Oct;55(10):1387-9
references: 16966698
references: Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G499-509
references: 19147804
references: J Biol Chem. 1998 Aug 7;273(32):20417-24
references: 9685395
references: Prostate. 2011 Jan 1;71(1):1-17
references: 20564325
references: J Alzheimers Dis. 2010;20(4):997-1002
references: 20413874
references: Biochem J. 2007 Jan 1;401(1):1-11
references: 17150040
references: Gene. 2013 Mar 1;516(1):76-81
references: 23266799
references: Korean J Urol. 2012 Mar;53(3):200-5
references: 22468217
references: Gene. 2012 Apr 15;497(2):273-9
references: 22310383
references: EXS. 1992;62:31-46
references: 1450594
references: Tumori. 2010 Jan-Feb;96(1):138-42
references: 20437871
references: Environ Toxicol. 2009 Aug;24(4):377-87
references: 18825727
references: J Nutr. 1991 Dec;121(12):1955-9
references: 1941259
references: Am J Clin Nutr. 2007 Aug;86(2):514-21
references: 17684227
references: Cell Biochem Biophys. 2011 Dec;61(3):715-23
references: 21792634
references: J Clin Biochem Nutr. 2012 Jan;50(1):35-9
references: 22247598
references: Anal Biochem. 1966 Aug;16(2):359-64
references: 6007581
references: Clin Chem. 2009 Mar;55(3):559-67
references: 19131636
references: Biochem J. 2006 Aug 15;398(1):73-82
references: 16626305
references: Brain Res. 2008 Oct 27;1237:44-51
references: 18694737
references: Nat Rev Genet. 2009 Apr;10(4):264-9
references: 19238176
references: Cancer Res. 2001 Sep 15;61(18):6669-73
references: 11559532
references: Arch Biochem Biophys. 1959 May;82(1):70-7
references: 13650640
references: Mod Pathol. 2008 Dec;21(12):1421-7
references: 18839017
references: PLoS One. 2011 Feb 25;6(2):e17017
references: 21364923
references: Mol Cell Biochem. 2012 Feb;361(1-2):189-95
references: 21987236
references: Oncogene. 2001 Mar 22;20(12):1509-18
references: 11313894
references: Circ Res. 2000 Jun 9;86(11):1129-34
references: 10850963
references: Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):511-9
references: 15066913
references: Adv Exp Med Biol. 2012;724:278-90
references: 22411250
references: Carcinogenesis. 2007 Jul;28(7):1504-9
references: 17372271
references: Ann Surg. 2001 Jul;234(1):10-20
references: 11420478
references: Gastroenterology. 1996 Apr;110(4):991-8
references: 8613033
references: Carcinogenesis. 2003 May;24(5):883-9
references: 12771032
references: Oncogene. 2002 Oct 3;21(44):6835-40
references: 12360410
references: Arch Med Res. 2011 Apr;42(3):182-8
references: 21722812
references: Antioxid Redox Signal. 2000 Winter;2(4):903-17
references: 11213491
references: Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H2025-31
references: 18790835
references: Cancer Res. 2002 Jun 15;62(12):3498-502
references: 12067994
references: Int Urol Nephrol. 2004;36(1):57-62
references: 15338676
references: Biomark Cancer. 2010 Feb 18;2:17-33
references: 24179382
references: Medicina (Kaunas). 2011;47(3):147-53
references: 21822036
references: J Carcinog. 2012;11:3
references: 22438769
references: Clin Cancer Res. 2002 Feb;8(2):514-9
references: 11839671
references: Apoptosis. 2012 Jan;17(1):14-24
references: 21938476
references: Am J Clin Nutr. 2008 Mar;87(3):517-33
references: 18326588