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Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro

Abstract

Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and linked to radio- and chemotherapy response as well as longer survival. The molecular mechanisms underlying this clinically important association are as yet unknown. Here, we studied the peroxiredoxin 1 (PRDX1) gene at 1p34.1 for promoter methylation and expression in primary gliomas and investigated its role in radio- and chemosensitivity of glioma cells in vitro. In total, we screened primary glioma tissues from 93 patients for methylation of the 5′-CpG island of PRDX1 by sodium bisulfite sequencing. PRDX1 mRNA and protein expression levels were determined in subsets of the tumours by quantitative PCR and western blot analysis, respectively. PRDX1 hypermethylation and reduced expression were frequently detected in oligodendroglial tumours and secondary glioblastomas, but not in primary glioblastomas. In oligodendroglial tumours, both PRDX1 hypermethylation and reduced mRNA expression were significantly associated with 1p/19q-deletion. Stable knockdown of PRDX1 by lentiviral transduction of short-hairpin (sh)RNA constructs significantly increased apoptosis and reduced cell viability of Hs683 glioma cells exposed to ionizing irradiation or temozolomide in vitro. Taken together, our findings indicate that epigenetic silencing of PRDX1 is frequent in 1p/19q-deleted oligodendroglial tumours and likely contributes to radio- and chemosensitivity of these tumours.

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References

  • Bae JY, Ahn SJ, Han W, Noh DY . (2007). Peroxiredoxin I and II inhibit H2O2-induced cell death in MCF-7 cell lines. J Cell Biochem 101: 1038–1045.

    Article  CAS  Google Scholar 

  • Baylin SB, Esteller M, Rountree MR, Bachman KE, Schuebel K, Herman JG . (2001). Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 10: 687–692.

    Article  CAS  Google Scholar 

  • Belot N, Rorive S, Doyen I, Lefranc F, Bruyneel E, Dedecker R et al. (2001). Molecular characterization of cell substratum attachments in human glial tumors relates to prognostic features. Glia 36: 375–390.

    Article  CAS  Google Scholar 

  • Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH et al. (2011). Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333: 1453–1455.

    Article  CAS  Google Scholar 

  • Brada M, Viviers L, Abson C, Hines F, Britton J, Ashley S et al. (2003). Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol 14: 1715–1721.

    Article  CAS  Google Scholar 

  • Branle F, Lefranc F, Camby I, Jeuken J, Geurts-Moespot A, Sprenger S et al. (2002). Evaluation of the efficiency of chemotherapy in in vivo orthotopic models of human glioma cells with and without 1p19q deletions and in C6 rat orthotopic allografts serving for the evaluation of surgery combined with chemotherapy. Cancer 95: 641–655.

    Article  CAS  Google Scholar 

  • Cairncross G, Berkey B, Shaw E, Jenkins R, Scheithauer B, Brachman D et al. (2006). Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol 24: 2707–2714.

    Article  CAS  Google Scholar 

  • Camby I, Bruyneel E, Geurts A, Decaestecker C, Sweep F, Brotchi J et al. (2000). Do human oligodendroglial and astroglial tumors derive from mature oligodendrocytes and astrocytes,or from precursor glial cells? Brain Pathol 10: 569.

    Google Scholar 

  • Cao J, Schulte J, Knight A, Leslie NR, Zagozdzon A, Bronson R et al. (2009). Prdx1 inhibits tumourigenesis via regulating PTEN/AKT activity. EMBO J 28: 1505–1517.

    Article  CAS  Google Scholar 

  • Felsberg J, Erkwoh A, Sabel MC, Kirsch L, Fimmers R, Blaschke B et al. (2004). Oligodendroglial tumours: refinement of candidate regions on chromosome arm 1p and correlation of 1p/19q status with survival. Brain Pathol 14: 121–130.

    Article  CAS  Google Scholar 

  • Felsberg J, Wolter M, Seul H, Friedensdorf B, Göppert M, Sabel MC et al. (2010). Rapid and sensitive assessment of the IDH1 and IDH2 mutation status in cerebral gliomas based on DNA pyrosequencing. Acta Neuropathol 119: 501–507.

    Article  CAS  Google Scholar 

  • Grzendowski M, Riemenschneider MJ, Hawranke E, Stefanski A, Meyer HE, Reifenberger G et al. (2009). Simultaneous extraction of nucleic acids and proteins from tissue specimens by ultracentrifugation: a protocol using the high-salt protein fraction for quantitative proteome analysis. Proteomics 9: 4985–4990.

    Article  CAS  Google Scholar 

  • Grzendowski M, Wolter M, Riemenschneider MJ, Knobbe CB, Schlegel U, Meyer HE et al. (2010). Differential proteome analysis of human gliomas stratified for loss of heterozygosity on chromosomal arms 1p and 19q. Neuro Oncol 12: 243–256.

    Article  CAS  Google Scholar 

  • Griffin CA, Burger P, Morsberger L, Yonescu R, Swierczynski S, Weingart JD et al. (2006). Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 65: 988–994.

    Article  Google Scholar 

  • Hattori F, Oikawa S . (2007). Peroxiredoxins in the central nervous system, in Peroxiredoxin Systems. In: Flohe L, Harris JR (eds). Structures and Functions. Springer: New York, 44: 357–374.

    Google Scholar 

  • Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al. (2005). MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352: 997–1003.

    Article  CAS  Google Scholar 

  • Hermisson M, Klumpp A, Wick W, Wischhusen J, Nagel G, Roos W et al. (2006). O6-methylguanine DNA methyltransferase and p53 status predict temozolomide sensitivity in human malignant glioma cells. J Neurochem 96: 766–776.

    Article  CAS  Google Scholar 

  • Hubstenberger A, Labourdette G, Baudier J, Rousseau D . (2008). ATAD 3A and ATAD 3B are distal 1p-located genes differentially expressed in human glioma cell lines and present in vitro anti-oncogenic and chemoresistant properties. Exp Cell Res 314: 2870–2883.

    Article  CAS  Google Scholar 

  • Immenschuh S, Baumgart-Vogt E . (2005). Peroxiredoxins, oxidative stress, and cell proliferation. Antioxid Redox Signal 7: 768–777.

    Article  CAS  Google Scholar 

  • Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M et al. (2006). A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66: 9852–9861.

    Article  CAS  Google Scholar 

  • Kim YJ, Lee WS, Ip C, Chae HZ, Park EM, Park YM . (2006). Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex. Cancer Res 66: 7136–7142.

    Article  CAS  Google Scholar 

  • Korshunov A, Neben K, Wrobel G, Tews B, Benner A, Hahn M et al. (2003). Gene expression patterns in ependymomas correlate with tumour location, grade, and patient age. Am J Pathol 163: 1721–1727.

    Article  CAS  Google Scholar 

  • Kouwenhoven MC, Kros JM, French PJ, Biemond-ter Stege EM, Graveland WJ, Taphoorn MJ et al. (2006). 1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment. Eur J Cancer 42: 2499–2503.

    Article  CAS  Google Scholar 

  • Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al. (2007). The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114: 97–109.

    Article  Google Scholar 

  • Mates JM, Segura JA, Alonso FJ, Marquez J . (2008). Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis. Arch Toxicol 82: 273–299.

    Article  CAS  Google Scholar 

  • Moffat J, Grueneberg DA, Yang X, Kim SY, Kloepfer AM, Hinkle G et al. (2006). A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124: 1283–1298.

    Article  CAS  Google Scholar 

  • Mollemann M, Wolter M, Felsberg J, Collins VP, Reifenberger G . (2005). Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumours. Int J Cancer 113: 379–385.

    Article  Google Scholar 

  • Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL et al. (2003). Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression. Nature 424: 561–565.

    Article  CAS  Google Scholar 

  • Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP et al. (2010). Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17: 510–522.

    Article  CAS  Google Scholar 

  • Ohgaki H, Kleihues P . (2009). Genetic alterations and signaling pathways in the evolution of gliomas. Cancer Sci 100: 2235–2241.

    Article  CAS  Google Scholar 

  • Reifenberger G, Louis DN . (2003). Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J Neuropathol Exp Neurol 62: 111–126.

    Article  CAS  Google Scholar 

  • Riemenschneider MJ, Reifenberger G . (2009). Novel insights into the pathogenesis of gliomas based on large-scale molecular profiling approaches. Curr Opin Neurol 22: 619–624.

    Article  CAS  Google Scholar 

  • Tews B, Felsberg J, Hartmann C, Kunitz A, Hahn M, Toedt G et al. (2006). Identification of novel oligodendroglioma-associated candidate tumour suppressor genes in 1p36 and 19q13 using microarray-based expression profiling. Int J Cancer 119: 792–800.

    Article  CAS  Google Scholar 

  • Tews B, Roerig P, Hartmann C, Hahn M, Felsberg J, Blaschke B et al. (2007). Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q. Oncogene 26: 5010–5016.

    Article  CAS  Google Scholar 

  • Trachootham D, Alexandre J, Huang P . (2009). Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8: 579–591.

    Article  CAS  Google Scholar 

  • van den Bent MJ . (2006). Adjuvant treatment of high grade gliomas. Ann Oncol 17: x186–x190.

    Article  Google Scholar 

  • van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K et al. (2005). Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366: 985–990.

    Article  CAS  Google Scholar 

  • van den Boom J, Wolter M, Kuick R, Misek DE, Youkilis AS, Wechsler DS et al. (2003). Characterization of gene expression profiles associated with glioma progression using oligonucleotide-based microarray analysis and real-time reverse transcription-polymerase chain reaction. Am J Pathol 163: 1033–1043.

    Article  CAS  Google Scholar 

  • Wang T, Tamae D, LeBon T, Shively JE, Yen Y, Li JJ . (2005). The role of peroxiredoxin II in radiation-resistant MCF-7 breast cancer cells. Cancer Res 65: 10338–10346.

    Article  CAS  Google Scholar 

  • Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W et al. (2010). MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6: 39–51.

    Article  CAS  Google Scholar 

  • Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F et al. (2009). NOA-04 randomised phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27: 5874–5880.

    Article  CAS  Google Scholar 

  • Zhang B, Wang Y, Liu K, Yang X, Song M, Bai Y . (2008). Adenovirus-mediated transfer of siRNA against peroxiredoxin I enhances the radiosensitivity of human intestinal cancer. Biochem Pharmacol 75: 660–667.

    Article  CAS  Google Scholar 

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Acknowledgements

The study was supported by the German Federal Ministry of Education and Research (BMBF) within the National Genome Research Network NGFN2 (01GS0460 to PL, 01GS0462 to GR), NGFNplus (01GS0883 to PL, 01GS0884 to GR and MW, 01GS08186 to KS) and the Ministry for Innovation, Science, Research and Technology (MIWFT) of Nordrhein Westfalen (MG). JG and JB were supported by scholarships from the Helmholtz international graduate school for cancer research.

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Correspondence to P Lichter.

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Dittmann, L., Danner, A., Gronych, J. et al. Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro. Oncogene 31, 3409–3418 (2012). https://doi.org/10.1038/onc.2011.513

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