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The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer

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Abstract

Loss of cell cycle control is a prerequisite for cancer onset and progression. In prostate cancer, increased activity of cell cycle genes has been associated with prognostic parameters such as biochemical relapse and survival. The identification of novel oncogenic and druggable targets in patient subgroups with poor prognosis may help to develop targeted therapy approaches. We analyzed prostate cancer and corresponding benign tissues (n = 98) using microarrays. The comparison of high- and low-grade tumors (Gleason score ≥ 4 + 3 vs. ≤ 3 + 4) revealed 144 differentially expressed genes (p < 0.05). Out of these, 15 genes were involved in the cell cycle process. The gene maternal embryonic leucine zipper kinase (MELK) was identified to be highly correlated with cell cycle genes like UBE2C, TOP2A, CCNB2, and AURKB. Increased MELK gene expression in high-risk prostate cancer was validated by qPCR in an independent patient cohort (p < 0.005, n = 79). Immunohistochemistry analysis using a tissue microarray (n = 94) revealed increased MELK protein expression in prostate cancer tissues of high Gleason scores. RNAi-based inhibition of MELK in PC3 and LNCaP cells suggested putative function in chromatin modification, embryonic development and cell migration. The concerted inhibition of MELK and other cell cycle targets by the antibiotic siomycin A strongly impaired cell viability of prostate cancer cells, and may point to a novel therapy approach for a subset of high-risk prostate cancer patients.

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References

  1. Strope SA, Andriole GL (2010) Prostate cancer screening: current status and future perspectives. Nat Rev Urol 7:487–493

    Article  PubMed  Google Scholar 

  2. Stark JR, Perner S, Stampfer MJ, Sinnott JA, Finn S, Eisenstein AS, Ma J, Fiorentino M, Kurth T, Loda M et al (2009) Gleason score and lethal prostate cancer: does 3 + 4 = 4 + 3? J Clin Oncol 27:3459–3464

    Article  PubMed  Google Scholar 

  3. Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, Mesher D, Speights VO, Stankiewicz E, Foster CS et al (2011) Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol 12:245–255

    Article  PubMed  CAS  Google Scholar 

  4. Tomlins SA, Laxman B, Dhanasekaran SM, Helgeson BE, Cao X, Morris DS, Menon A, Jing X, Cao Q, Han B et al (2007) Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature 448:595–599

    Article  PubMed  CAS  Google Scholar 

  5. Gray D, Jubb AM, Hogue D, Dowd P, Kljavin N, Yi S, Bai W, Frantz G, Zhang Z, Koeppen H et al (2005) Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers. Cancer Res 65:9751–9761

    Article  PubMed  CAS  Google Scholar 

  6. Marie SK, Okamoto OK, Uno M, Hasegawa AP, Oba-Shinjo SM, Cohen T, Camargo AA, Kosoy A, Carlotti CG Jr, Toledo S et al (2008) Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int J Cancer 122:807–815

    Article  PubMed  CAS  Google Scholar 

  7. Pickard MR, Green AR, Ellis IO, Caldas C, Hedge VL, Mourtada-Maarabouni M, Williams GT (2009) Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res 11:R60

    Article  PubMed  Google Scholar 

  8. Ryu B, Kim DS, Deluca AM, Alani RM (2007) Comprehensive expression profiling of tumor cell lines identifies molecular signatures of melanoma progression. PLoS One 2:e594

    Article  PubMed  Google Scholar 

  9. Nakano I, Joshi K, Visnyei K, Hu B, Watanabe M, Lam D, Wexler E, Saigusa K, Nakamura Y, Laks DR et al (2011) Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway. Neuro Oncol 13:622–634

    Article  PubMed  CAS  Google Scholar 

  10. Heyer BS, Kochanowski H, Solter D (1999) Expression of Melk, a new protein kinase, during early mouse development. Dev Dyn 215:344–351

    Article  PubMed  CAS  Google Scholar 

  11. Le Page Y, Chartrain I, Badouel C, Tassan JP (2011) A functional analysis of MELK in cell division reveals a transition in the mode of cytokinesis during Xenopus development. J Cell Sci 124:958–968

    Article  PubMed  Google Scholar 

  12. Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:67

    Article  PubMed  Google Scholar 

  13. Nakano I, Paucar AA, Bajpai R, Dougherty JD, Zewail A, Kelly TK, Kim KJ, Ou J, Groszer M, Imura T et al (2005) Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J Cell Biol 170:413–427

    Article  PubMed  CAS  Google Scholar 

  14. Hebbard LW, Maurer J, Miller A, Lesperance J, Hassell J, Oshima RG, Terskikh AV (2010) Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo. Cancer Res 70:8863–8873

    Article  PubMed  CAS  Google Scholar 

  15. Nakano I, Masterman-Smith M, Saigusa K, Paucar AA, Horvath S, Shoemaker L, Watanabe M, Negro A, Bajpai R, Howes A et al (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res 86:48–60

    Article  PubMed  CAS  Google Scholar 

  16. Oberaigner W, Siebert U, Horninger W, Klocker H, Bektic J, Schafer G, Frauscher F, Schennach H, Bartsch G (2012) Prostate-specific antigen testing in Tyrol, Austria: prostate cancer mortality reduction was supported by an update with mortality data up to 2008. Int J Public Health 57(1):57–62

    Article  PubMed  Google Scholar 

  17. Bu H, Bormann S, Schafer G, Horninger W, Massoner P, Neeb A, Lakshmanan VK, Maddalo D, Nestl A, Sultmann H et al (2011) The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection. Prostate 71:575–587

    Article  PubMed  CAS  Google Scholar 

  18. Du P, Kibbe WA, Lin SM (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24:1547–1548

    Article  PubMed  CAS  Google Scholar 

  19. Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3, Article 3

  20. Beissbarth T, Speed TP (2004) GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 20:1464–1465

    Article  PubMed  CAS  Google Scholar 

  21. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B et al (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18:11–22

    Article  PubMed  CAS  Google Scholar 

  22. Pressinotti NC, Klocker H, Schafer G, Luu VD, Ruschhaupt M, Kuner R, Steiner E, Poustka A, Bartsch G, Sultmann H (2009) Differential expression of apoptotic genes PDIA3 and MAP3K5 distinguishes between low- and high-risk prostate cancer. Mol Cancer 8:130

    Article  PubMed  Google Scholar 

  23. Detre S, Saclani Jotti G, Dowsett M (1995) A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol 48:876–878

    Article  PubMed  CAS  Google Scholar 

  24. Lotan TL, Epstein JI (2010) Clinical implications of changing definitions within the Gleason grading system. Nat Rev Urol 7:136–142

    Article  PubMed  Google Scholar 

  25. Penney KL, Sinnott JA, Fall K, Pawitan Y, Hoshida Y, Kraft P, Stark JR, Fiorentino M, Perner S, Finn S et al (2011) mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol 29:2391–2396

    Article  PubMed  CAS  Google Scholar 

  26. Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR, Hoshida Y, Mosquera JM, Pawitan Y, Lee C et al (2007) TMPRSS2: ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26:4596–4599

    Article  PubMed  CAS  Google Scholar 

  27. Haussler O, Epstein JI, Amin MB, Heitz PU, Hailemariam S (1999) Cell proliferation, apoptosis, oncogene, and tumor suppressor gene status in adenosis with comparison to benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and cancer. Hum Pathol 30:1077–1086

    Article  PubMed  CAS  Google Scholar 

  28. Reddy SK, Rape M, Margansky WA, Kirschner MW (2007) Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation. Nature 446:921–925

    Article  PubMed  CAS  Google Scholar 

  29. Badouel C, Korner R, Frank-Vaillant M, Couturier A, Nigg EA, Tassan JP (2006) M-phase MELK activity is regulated by MPF and MAPK. Cell Cycle 5:883–889

    Article  PubMed  CAS  Google Scholar 

  30. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J, Chen Z, Beroukhim R, Wang H, Lupien M et al (2009) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138:245–256

    Article  PubMed  CAS  Google Scholar 

  31. Wang L, Tang H, Thayanithy V, Subramanian S, Oberg AL, Cunningham JM, Cerhan JR, Steer CJ, Thibodeau SN (2009) Gene networks and microRNAs implicated in aggressive prostate cancer. Cancer Res 69:9490–9497

    Article  PubMed  CAS  Google Scholar 

  32. Pandit B, Gartel AL (2010) New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancer. Prostate 70:825–833

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Denise Keitel, Marcello Schifani, Christof Seifarth, Birgit Stenzel, and Irma Sottsas for excellent technical assistance. We thank the DKFZ core facility for the microarray service. This study was supported by a grant of the Austrian Nationalstiftung and the Austria Wirtschaftsservice GmbH in the framework of the IMGuS research program (Institute for Medical Genome Research and Systems Biology, Wien).

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The authors declare no conflict of interest.

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Author notes

  1. Maria Fälth

    Present address: Cellzome AG, Heidelberg, Germany

  2. Nicole Chui Pressinotti

    Present address: Abbott GmbH and Co.KG, Wiesbaden, Germany

  3. Jan C. Brase

    Present address: Sividon Diagnostics GmbH, Cologne, Germany

Authors and Affiliations

  1. Unit Cancer Genome Research, Division of Molecular Genetics, German Cancer Research Center and National Center of Tumor Diseases, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany

    Ruprecht Kuner, Maria Fälth, Nicole Chui Pressinotti, Jan C. Brase, Sabrina Balaguer Puig, Jennifer Metzger, Stephan Gade & Holger Sültmann

  2. Department of Urology, Innsbruck Medical University, Innsbruck, Austria

    Georg Schäfer, Georg Bartsch, Eberhard Steiner & Helmut Klocker

  3. Institute for Pathology, Innsbruck Medical University, Innsbruck, Austria

    Georg Schäfer

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  1. Ruprecht Kuner
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Correspondence to Ruprecht Kuner.

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Kuner, R., Fälth, M., Pressinotti, N.C. et al. The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer. J Mol Med 91, 237–248 (2013). https://doi.org/10.1007/s00109-012-0949-1

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  • DOI: https://doi.org/10.1007/s00109-012-0949-1

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