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Correlation between 5-α reductase type 2 protein expression and methylation of 5-α reductase type 2 promotor gene of benign prostatic hyperplasia

World Journal of Urology volume 37, pages 709–718 (2019)Cite this article

Abstract

Purpose

The enzyme 5-α reductase type 2 (5-AR 2) plays a key role in the development and maintenance of the prostate gland. We evaluated the level 5-AR 2 protein expression and the relationship between methylation of the 5-AR 2 gene-promoter and 5-AR 2 protein expression of benign prostatic hyperplasia (BPH).

Materials and methods

A total of 37 prostate samples were evaluated. These included 22 samples from men undergoing transurethral prostate resections and 15 non-cancerous transition-zone human prostate tissue samples taken following radical prostatectomy. We quantified 5-AR 2 protein expression and gene-promoter methylation status using common assay procedures. Clinical variables included age, body mass index (BMI), prostate-specific antigen (PSA) levels, lipid profiles, and prostate volumes. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling.

Results

We were able to extract DNA from 36 of the 37 tissue samples and 10 of these (28%) did not express the 5-AR 2 protein. In total, 26 patients (72%) had methylated 5-AR 2 promoter-regions. There was a strong correlation between methylation of the 5-AR 2 promoter-regions and low-absent 5-AR 2 protein expression (p = 0.0003). Increasing age significantly predicted methylation status and protein expression level (p = 0.013).

Conclusions

The level of 5-AR 2 protein expression varies among prostate tissue samples. Methylation of the 5-AR 2 gene-promoter may account for low or absent expression of 5-AR 2 in adult human prostate tissues. Increased age correlates with increased 5-AR 2 gene-promoter methylation and decreased protein expression in men with BPH.

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References

  1. Roehrborn CG (2008) Pathology of benign prostatic hyperplasia. Int J Impot Res 20(Suppl 3):S8–S11

    Google Scholar 

  2. Berry SJ, Coffey DS, Walsh PC, Ewing LL (1984) The development of human benign prostatic hyperplasia with age. J Urol 132(3):474–479

    Article  CAS  PubMed  Google Scholar 

  3. Shapiro E, Becich MJ, Hartanto V, Lepor H (1992) The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia. J Urol 147(5):1293–1297

    Article  CAS  PubMed  Google Scholar 

  4. Marcelli M, Cunningham GR (1999) Hormonal signaling in prostatic hyperplasia and neoplasia. J Clin Endocrinol Metab 84(10):3463–3468

    CAS  PubMed  Google Scholar 

  5. Langlois VS, Zhang D, Cooke GM, Trudeau VL (2010) Evolution of steroid 5-alpha reductases and comparison of their function with 5-beta reductase. Gen Comp Endocrinol 166(3):489–497

    Article  CAS  PubMed  Google Scholar 

  6. Azzouni F, Godoy A, Li Y, Mohler J (2012) The 5-alpha reductase isozyme family: a review of the basic biology and their role in human diseases. Adv Urol 2012:530121

    Article  PubMed  Google Scholar 

  7. Russell DW, Wilson JD (1994) Steroid 5-alpha reductase: two genes/two enzymes. Ann Rev Biochem 63:25–61

    Article  CAS  PubMed  Google Scholar 

  8. Carson C, Rittmaster R (2003) The role of dihydrotestosterone in benign prostatic hyperplasia. Urology 61(4 Suppl. 1):2–7

    Article  PubMed  Google Scholar 

  9. Xu Y, Dalrymple SL, Becker RE, Denmeade SR, Isaacs JT (2006) Pharmacologic basis for the enhanced efficacy of dutasteride against prostate cancers. Clin Cancer Res 12(13):4072–4079

    Article  CAS  PubMed  Google Scholar 

  10. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL et al (1998) The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 338:557–563

    Article  CAS  PubMed  Google Scholar 

  11. Roehrborn CG, Lukkarinen O, Mark S, Siami P, Ramsdell J, Zinner N (2005) Long-term sustained improvement in symptoms of benign prostatic hyperplasia with the dual 5-alpha reductase inhibitor dutasteride: results of 4-year studies. BJU Int 96(4):572–577

    Article  CAS  PubMed  Google Scholar 

  12. Andriole GL, Guess HA, Epstein JI, Wise H, Kadmon D, Crawford ED (1998) Treatment with finasteride preserves usefulness of prostate-specific antigen in the detection of prostate cancer: results of a randomized, double-blind, placebo-controlled clinical trial. PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology 52(2):195–202

    Article  CAS  PubMed  Google Scholar 

  13. Hong SJ, Ko WJ, Kim SI, Chung BH (2003) Identification of baseline clinical factors which predict medical treatment failure of benign prostatic hyperplasia: an observational cohort study. Eur Urol 44(1):94–99

    Article  PubMed  Google Scholar 

  14. Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bechis SK, Otsetov AG, Ge R, Olumi AF (2014) Personalized medicine for management of benign prostatic hyperplasia. J Urol 192(1):16–23

    Article  PubMed  PubMed Central  Google Scholar 

  17. Steers WD (2001) 5-alpha reductase activity in the prostate. Urology 58(6 Suppl 1):17–24

    Article  CAS  PubMed  Google Scholar 

  18. Walsh PC, Madden JD, Harrod MJ, Goldstein JL, MacDonald PC, Wilson JD (1974) Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 291(18):944–949

    Article  CAS  PubMed  Google Scholar 

  19. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE (1974) Steroid 5-alpha reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 186(4170):1213–1215

    Article  CAS  PubMed  Google Scholar 

  20. Niu Y, Ge R, Hu L, Diaz C, Wang Z, Wu CL et al (2011) Reduced levels of 5-a reductase 2 in adult prostate tissue and implications for BPH therapy. Prostate 71(12):1317–1324

    CAS  PubMed  Google Scholar 

  21. Bechis SK, Otsetov AG, Ge R, Wang Z, Vangel MG, Wu CL et al (2015) Age and obesity promote methylation and suppression of 5-α reductase 2: implications for personalized therapy of benign prostatic hyperplasia. J Urol 194(4):1031–1037

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dobosy JR, Roberts JL, Fu VX, Jarrard DF (2007) The expanding role of epigenetics in the development, diagnosis and treatment of prostate cancer and benign prostatic hyperplasia. J Urol 177(3):822–831

    Article  CAS  PubMed  Google Scholar 

  23. Bastian PJ, Ellinger J, Wellmann A, Wernert N, Heukamp LC, Müller SC et al (2005) Diagnostic and prognostic information in prostate cancer with the help of a small set of hypermethylated gene loci. Clin Cancer Res 11(11):4097–4106

    Article  CAS  PubMed  Google Scholar 

  24. Calvanese V, Lara E, Kahn A, Fraga MF (2009) The role of epigenetics in aging and age-related diseases. Ageing Res Rev 8(4):268–276

    Article  CAS  PubMed  Google Scholar 

  25. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358(11):1148–1159

    Article  CAS  PubMed  Google Scholar 

  26. Walsh PC, Madden JD, Harrod MJ, Goldstein JL, MacDonald PC, Wilson JD (1974) Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 291(18):944–949

    Article  CAS  PubMed  Google Scholar 

  27. Frazier-Wood AC, Aslibekyan S, Absher DM, Hopkins PN, Sha J, Tsai MY et al (2014) Methylation at CPT1A locus is associated with lipoprotein subfraction profiles. J Lipid Res 55(7):1324–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gagnon F, Aissi D, Carrie A, Morange PE, Tregouet DA (2014) Robust validation of methylation levels association at CPT1A locus with lipid plasma levels. J Lipid Res 55(7):89–91

    Article  CAS  Google Scholar 

  29. Pfeiffer L, Wahl S, Pilling LC, Reischl E, Sandling JK, Kunze S et al (2015) DNA methylation of lipid related genes affects blood lipid levels. Circ Cardiovasc Genet 8(2):334–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lamon-Fava S, Wilson PW, Schaefer EJ (1996) Impact of body mass index on coronary heart disease risk factors in men and women. The Framingham Offspring Study. Arterioscler Thromb Biol 16(12):1509–1515

    Article  CAS  Google Scholar 

  31. Brown C, Higgins M, Donato K, Rohde F, Garrison R, Obarzanek E et al (2000) Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res 8(9):605–619

    Article  CAS  PubMed  Google Scholar 

  32. Alexander J (2001) Obesity and coronary heart disease. Am J Med Sci 321(4):215–224

    Article  CAS  PubMed  Google Scholar 

  33. Gostynski M, Gutzwiller F, Kuulasmaa K, Döring A, Ferrario M, Grafnetter D et al (2004) Analysis of the relationship between total cholesterol, age, body mass index among males and females in the WHO MONICA Project. Int J Obes 28(8):1082–1090

    Article  CAS  Google Scholar 

  34. Benton MC, Johnstone A, Eccles D, Harmon B, Hayes MT, Lea RA et al (2015) An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss. Genome Biol 22(16):8

    Article  CAS  Google Scholar 

  35. Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aissi D, Wahl S et al (2014) DNA methylation and body-mass index: a genomewide analysis. Lancet 383(9933):1990–1998

    Article  CAS  PubMed  Google Scholar 

  36. Barres R, Kirchner H, Rasmussen M, Yan J, Kantor FR, Krook A et al (2013) Weight loss after gastric bypass surgery in human obesity remodels promoter methylation. Cell Rep 3(4):1020–1207

    Article  CAS  PubMed  Google Scholar 

  37. Issa JP (2014) Aging and epigenetic drift: a vicious cycle. J Clin Invest 124(1):24–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T et al (2010) Inflammatory processes triggered by helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res 70(4):1430–1440

    Article  CAS  PubMed  Google Scholar 

  39. Hahn MA, Hahn T, Lee DH, Esworthy RS, Kim BW, Riggs AD et al (2008) Methylation of polycomb target genes in intestinal cancer is mediated by inflammation. Cancer Res 68(24):10280–10289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim J, Kim JY, Song KS, Lee YH, Seo JS, Jelinek J et al (2007) Epigenetic changes in estrogen receptor beta gene in atherosclerotic cardiovascular tissues and in vitro vascular senescence. Biochim Biophys Acta 1772(1):72–80

    Article  CAS  PubMed  Google Scholar 

  41. Teitell M, Richardson B (2003) DNA methylation in the immune system. Clin Immunol 109(1):2–5

    Article  CAS  PubMed  Google Scholar 

  42. Thomas LN, Lazier CB, Gupta R, Norman RW, Troyer DA, O’Brien SP et al (2005) Differential alterations in 5alpha-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate 63(3):231–239

    Article  CAS  PubMed  Google Scholar 

  43. Titus MA, Gregory CW, Ford OH 3rd, Schell MJ, Maygarden SJ, Mohler JL (2005) Steroid 5alpha-reductase isozymes I and II in recurrent prostate cancer. Clin Cancer Res 11(12):4365–4371

    Article  CAS  PubMed  Google Scholar 

  44. Thomas LN, Douglas RC, Lazier CB, Too CK, Rittmaster RS, Tindall DJ (2008) Type 1 and type 2 5 alpha-reductase expression in the development and progression of prostate cancer. Eur Urol 53(2):244–252

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by a grant from Kosin University College of Medicine (2016) (to P.M.K), and also by Korea National Research Foundation (KNRF) grants 2015M3A9B6073646, 2015R1D1A1A01058387 and 2017M3A9G7072564 (to J.Y.J).

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Author notes

  1. Pil Moon Kang, Young Jin Kim, Jee-Yeong Jeong and Jae Il Chung contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Kosin Gospel Hospital, Kosin University College of Medicine, Busan, Korea

    Pil Moon Kang, Won Tae Seo, Su Hwan Kang & Taek Sang Kim

  2. Department of Biochemistry, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan, 49267, Korea

    Young Jin Kim & Jee-Yeong Jeong

  3. Cancer Research Institute, Kosin University College of Medicine, Busan, Korea

    Young Jin Kim & Jee-Yeong Jeong

  4. Department of Pathology, Kosin University College of Medicine, Busan, Korea

    Bong Kwon Chun

  5. Department of Urology, Busan Paik Hospital, Inje University College of Medicine, Gaegeum-dong, Busanjin-gu, Busan, 614-735, Korea

    Won Ik Seo & Jae Il Chung

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  1. Pil Moon Kang
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Contributions

PMK: first author, conception and design, drafting the manuscript, statistical analysis, YJK: co-first author (PMK and YJK contributed equally to the work) performed the experiments (Tissue processing, DNA extraction and methylation analysis), WTS: protocol/project development, data analysis, SHK: critical revision of the manuscript for scientific and factual content, TSK: critical revision of the manuscript for scientific and factual content, BKC: pathological examination, immunohistochemistry analysis, WIS: critical revision of the manuscript for scientific and factual content, JYJ: co-corresponding author (JYJ and JIC contributed equally to the work) contributed reagents/materials/analysis tools, JIC: conception and design, Supervision.

Corresponding authors

Correspondence to Jee-Yeong Jeong or Jae Il Chung.

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The author(s) declare that they have no competing interests.

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Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Kang, P.M., Kim, Y.J., Seo, W.T. et al. Correlation between 5-α reductase type 2 protein expression and methylation of 5-α reductase type 2 promotor gene of benign prostatic hyperplasia. World J Urol 37, 709–718 (2019). https://doi.org/10.1007/s00345-018-2422-4

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  • DOI: https://doi.org/10.1007/s00345-018-2422-4

Keywords

  • 5-α Reductase
  • DNA
  • Hyperplasia
  • Methylation
  • Prostate