title: MiR-26a and miR-138 block the G1/S transition by targeting the cell cycle regulating network in prostate cancer cells.
abstract: OBJECTIVE
  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.
authors: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany. kati.erdmann@uniklinikum-dresden.de.
authors: Kati
authors: http://orcid.org/0000-0003-3717-3637
authors: K
authors: Erdmann
authors: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Knut
authors: K
authors: Kaulke
authors: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Christiane
authors: C
authors: Rieger
authors: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Karsten
authors: K
authors: Salomo
authors: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Manfred P
authors: MP
authors: Wirth
authors: Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
authors: Susanne
authors: S
authors: Fuessel
mesh_terms: D040761:Biomimetic Materials / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D016196:S Phase / Q000235:genetics*; D014162:Transfection
chemical_list: D000071221:Enhancer of Zeste Homolog 2 Protein; D035683:MicroRNAs; D034741:RNA, Small Interfering; C546110:MIRN138 microRNA, human; C528163:MIRN26 microRNA, human; C498409:EZH2 protein, human
keywords: Cell cycle; Enhancer of zeste homolog 2 (EZH2); MiR-138; MiR-26a; MicroRNAs; Prostate cancer