@article{169f95d667d04844989929f1d4b393b1,
title = "Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER",
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.",
author = "{Van Den Beucken}, Twan and Elizabeth Koch and Kenneth Chu and Rajesha Rupaimoole and Peggy Prickaerts and Michiel Adriaens and Voncken, {Jan Willem} and Harris, {Adrian L.} and Buffa, {Francesca M.} and Syed Haider and Starmans, {Maud H.W.} and Yao, {Cindy Q.} and Mircea Ivan and Cristina Ivan and Pecot, {Chad V.} and Boutros, {Paul C.} and Sood, {Anil K.} and Marianne Koritzinsky and Wouters, {Bradly G.}",
note = "Funding Information: We thank R. Weinberg for providing the HMLER cells. We also thank C. Arrowsmith for providing the SGC inhibitors. We thank Alison Casey, Milan Ganguly and Trevor Do for advice and technical assistance on the immunohistochemical staining in these and other tissue samples. This work was financially supported by the Dutch Cancer Society (KWF grant UM 2008-4068 to B.W.), the Ontario Ministry of Health and Long Term Care (OMOHLTC), the Terry Fox New Frontiers Research Program PPG-1036 to B.G.W. and M.K.), the Ontario Institute for Cancer Research and Terry Fox Research Institute (Stem Cell Program to B.G.W.), the Canadian Institute for Health Research (CIHR grant 201592 to B.G.W. and M.K.) and the EU 7th framework programme (METOXIA project 222741 to B.G.W. and M.K.). The views expressed do not necessarily reflect those of the OMOHLTC. This study was conducted with the support of the Ontario Institute for Cancer Research to P.C.B. through funding provided by the Government of Ontario. E.K. and C.Q.Y. were supported by fellowships from the Canadian Breast Cancer Foundation (CBCF). A.L.H. was supported by funding from Cancer Research UK (CRUK_A11359) and the Breast Cancer Research Foundation (BCRF). A.K.S. was supported by funding from the National Institute of Health (U54 151668, P50 CA083639, and UH2 TR000943). M.I. was supported by funding from the National Institute of Health (R01 CA155332-01). This study makes use of data generated by the Molecular Taxonomy of Breast Cancer International Consortium34, which was funded by Cancer Research UK and the British Columbia Cancer Agency Branch. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",
year = "2014",
doi = "10.1038/ncomms6203",
language = "English (US)",
volume = "5",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}