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A paper by Elizabeth Koch et al on epigenetic regulation of ​DICER and stem cell phenotypes by hypoxia is published in Nature Communications.

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 & Bradly G. Wouters

 

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.