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GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD

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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.

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Acknowledgements

This work was supported by the grant funded by Indian Council of Medical Research (ICMR), New Delhi (Ref No. 5/13/32/2007), and Lady Tata Junior Research Fellowship awarded to Ms. Shree Divyya. We would also like to thank all the patients and the family members who participated in the study.

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Authors and Affiliations

  1. Departments of Clinical Pharmacology and Therapeutics, Nizam’s Institute of Medical Sciences (NIMS), Panjagutta, Hyderabad, 500082, India

    Shree Divyya, Shaik Mohammad Naushad & Vijay Kumar Kutala

  2. Departments of Urology, Nizam’s Institute of Medical Sciences, Hyderabad, India

    P. V. L. N. Murthy & Ch Ram Reddy

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  1. Shree Divyya
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  2. Shaik Mohammad Naushad
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  3. P. V. L. N. Murthy
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  5. Vijay Kumar Kutala
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Correspondence to Vijay Kumar Kutala.

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Divyya, S., Naushad, S.M., Murthy, P.V.L.N. et al. GCPII modulates oxidative stress and prostate cancer susceptibility through changes in methylation of RASSF1, BNIP3, GSTP1 and Ec-SOD . Mol Biol Rep 40, 5541–5550 (2013). https://doi.org/10.1007/s11033-013-2655-7

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