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

Research output: Contribution to journalArticle

106 Citations (Scopus)

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.

Original languageEnglish (US)
Article number5203
JournalNature communications
Volume5
DOIs
StatePublished - 2014

Fingerprint

phenotype
prognosis
stem cells
hypoxia
Stem cells
MicroRNAs
Epigenomics
Stem Cells
cancer
regulators
Phenotype
breast
tumors
biological evolution
Tumors
gene expression
oxygen
Breast Neoplasms
Oxygen
Epithelial-Mesenchymal Transition

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Van Den Beucken, T., Koch, E., Chu, K., Rupaimoole, R., Prickaerts, P., Adriaens, M., ... Wouters, B. G. (2014). Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nature communications, 5, [5203]. https://doi.org/10.1038/ncomms6203

Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. / Van Den Beucken, Twan; Koch, Elizabeth; Chu, Kenneth; Rupaimoole, Rajesha; Prickaerts, Peggy; Adriaens, Michiel; Voncken, Jan Willem; Harris, Adrian L.; Buffa, Francesca M.; Haider, Syed; Starmans, Maud H.W.; Yao, Cindy Q.; Ivan, Mircea; Ivan, Cristina; Pecot, Chad V.; Boutros, Paul C.; Sood, Anil K.; Koritzinsky, Marianne; Wouters, Bradly G.

In: Nature communications, Vol. 5, 5203, 2014.

Research output: Contribution to journalArticle

Van Den Beucken, T, Koch, E, Chu, K, Rupaimoole, R, Prickaerts, P, Adriaens, M, Voncken, JW, Harris, AL, Buffa, FM, Haider, S, Starmans, MHW, Yao, CQ, Ivan, M, Ivan, C, Pecot, CV, Boutros, PC, Sood, AK, Koritzinsky, M & Wouters, BG 2014, 'Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER', Nature communications, vol. 5, 5203. https://doi.org/10.1038/ncomms6203
Van Den Beucken, Twan ; Koch, Elizabeth ; Chu, Kenneth ; Rupaimoole, Rajesha ; Prickaerts, Peggy ; Adriaens, Michiel ; Voncken, Jan Willem ; Harris, Adrian L. ; Buffa, Francesca M. ; Haider, Syed ; Starmans, Maud H.W. ; Yao, Cindy Q. ; Ivan, Mircea ; Ivan, Cristina ; Pecot, Chad V. ; Boutros, Paul C. ; Sood, Anil K. ; Koritzinsky, Marianne ; Wouters, Bradly G. / Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. In: Nature communications. 2014 ; Vol. 5.
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