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MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells

  • Original Article – Cancer Research
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Abstract

Purpose

The tumor-suppressive microRNAs miR-26a and miR-138 are significantly down-regulated in prostate cancer (PCa) and have been identified as direct regulators of enhancer of zeste homolog 2 (EZH2), which is a known oncogene in PCa. In the present study, the influence of miR-26a and miR-138 on EZH2 and cellular function including the impact on the cell cycle regulating network was evaluated in PCa cells.

Methods

PC-3 and DU-145 PCa cells were transfected with 100 nM of miRNA mimics, siRNA against EZH2 (siR-EZH2) or control constructs for 4 h. Analyses of gene expression and cellular function were conducted 48 h after transfection.

Results

Both miRNAs influenced the EZH2 expression and activity only marginally, whereas siR-EZH2 led to a notable decrease of the EZH2 expression and activity. Both miRNAs inhibited short- and/or long-term proliferation of PCa cells but showed no effect on viability and apoptosis. In PC-3 cells, miR-26a and miR-138 caused a significant surplus of cells in the G0/G1 phase of 6 and 12 %, respectively, thus blocking the G1/S-phase transition. Treatment with siR-EZH2 was without substantial influence on cellular function and cell cycle. Therefore, alternative target genes involved in cell cycle regulation were identified in silico. MiR-26a significantly diminished the expression of its targets CCNE1, CCNE2 and CDK6, whereas CCND1, CCND3 and CDK6 were suppressed by their regulator miR-138.

Conclusions

The present findings suggest an anti-proliferative role for miR-26a and miR-138 in PCa by blocking the G1/S-phase transition independent of EZH2 but via a concerted inhibition of crucial cell cycle regulators.

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Acknowledgments

This work was funded by the Wilhelm Sander-Foundation (Grant No.: 2010.041.1). Kati Erdmann and Karsten Salomo also received financial support from the Förderverein Hilfe bei Prostatakrebs e.V. (Movember Campaign; Grant No.: MOV-2013-06). Furthermore, the authors are grateful to Dr. Matthias Kotzsch, Andrea Lohse-Fischer and Ulrike Lotzkat for their excellent technical assistance.

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    1. Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany

      Kati Erdmann, Knut Kaulke, Christiane Rieger, Karsten Salomo, Manfred P. Wirth & Susanne Fuessel

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    1. Kati Erdmann
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    2. Knut Kaulke
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    Correspondence to Kati Erdmann.

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    Kati Erdmann and Knut Kaulke have contributed equally to this work.

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    Erdmann, K., Kaulke, K., Rieger, C. et al. MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells. J Cancer Res Clin Oncol 142, 2249–2261 (2016). https://doi.org/10.1007/s00432-016-2222-4

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