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

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. Starmans, Cindy Q. Yao, Mircea Ivan, Cristina Ivan, Chad V. Pecot, Paul C. Boutros, Anil K. Sood, Marianne Koritzinsky and Bradly G. Wouters ()
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Twan van den Beucken: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
Elizabeth Koch: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
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
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
Cindy Q. Yao: University of Toronto
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
Anil K. Sood: The University of Texas MD Anderson Cancer Center
Marianne Koritzinsky: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network
Bradly G. Wouters: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6203

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