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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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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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