Document Detail

Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER.
MedLine Citation:
PMID:  25351418     Owner:  NLM     Status:  In-Data-Review    
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.
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
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Publication Detail:
Type:  Journal Article     Date:  2014-10-29
Journal Detail:
Title:  Nature communications     Volume:  5     ISSN:  2041-1723     ISO Abbreviation:  Nat Commun     Publication Date:  2014  
Date Detail:
Created Date:  2014-10-29     Completed Date:  -     Revised Date:  2014-12-05    
Medline Journal Info:
Nlm Unique ID:  101528555     Medline TA:  Nat Commun     Country:  England    
Other Details:
Languages:  eng     Pagination:  5203     Citation Subset:  IM    
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