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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER

Author

Listed:
  • Twan van den Beucken

    (Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
    GROW School for Oncology and Developmental Biology, Maastricht University Medical Center
    GROW School for Oncology and Developmental Biology, Maastricht University Medical Center)

  • Elizabeth Koch

    (Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
    University of Toronto)

  • Kenneth Chu

    (Informatics and Bio-computing Program, Ontario Institute for Cancer Research)

  • Rajesha Rupaimoole

    (The University of Texas MD Anderson Cancer Center)

  • Peggy Prickaerts

    (GROW School for Oncology and Developmental Biology, Maastricht University Medical Center)

  • Michiel Adriaens

    (Heart Failure Research Centre, Academic Medical Center
    Maastricht University)

  • Jan Willem Voncken

    (GROW School for Oncology and Developmental Biology, Maastricht University Medical Center)

  • Adrian L. Harris

    (The Weatherall Institute of Molecular Medicine, John Radcliffe Hospital)

  • Francesca M. Buffa

    (The Weatherall Institute of Molecular Medicine, John Radcliffe Hospital)

  • Syed Haider

    (Informatics and Bio-computing Program, Ontario Institute for Cancer Research)

  • Maud H. W. Starmans

    (GROW School for Oncology and Developmental Biology, Maastricht University Medical Center
    Informatics and Bio-computing Program, Ontario Institute for Cancer Research)

  • Cindy Q. Yao

    (University of Toronto
    Informatics and Bio-computing Program, Ontario Institute for Cancer Research)

  • Mircea Ivan

    (The Indiana University Melvin and Bren Simon Cancer Center)

  • Cristina Ivan

    (Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center)

  • Chad V. Pecot

    (Head and Neck Oncology, The University of Texas MD Anderson Cancer Center)

  • Paul C. Boutros

    (University of Toronto
    Informatics and Bio-computing Program, Ontario Institute for Cancer Research
    University of Toronto)

  • Anil K. Sood

    (The University of Texas MD Anderson Cancer Center
    Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center)

  • Marianne Koritzinsky

    (Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
    Institute of Medical Science, University of Toronto
    University of Toronto)

  • Bradly G. Wouters

    (Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
    GROW School for Oncology and Developmental Biology, Maastricht University Medical Center
    University of Toronto
    University of Toronto)

Abstract

MicroRNAs are small regulatory RNAs that post transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet, the underlying mechanisms are not well understood. Here we identify tumour hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumour stem cell phenotypes that may underlie poor outcome in breast cancer.

Suggested Citation

  • Twan van den Beucken & Elizabeth Koch & Kenneth Chu & Rajesha Rupaimoole & Peggy Prickaerts & Michiel Adriaens & Jan Willem Voncken & Adrian L. Harris & Francesca M. Buffa & Syed Haider & Maud H. W. S, 2014. "Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6203
    DOI: 10.1038/ncomms6203
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