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.
authors.affiliation: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Radiation Oncology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD, Maastricht, The Netherlands.|Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD, Maastricht, The Netherlands.
authors.forename: Twan
authors.initials: T
authors.lastname: van den Beucken
authors.affiliation: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Koch
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Chu
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rajesha
authors.initials: R
authors.lastname: Rupaimoole
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD, Maastricht, The Netherlands.
authors.forename: Peggy
authors.initials: P
authors.lastname: Prickaerts
authors.affiliation: Department of Experimental Cardiology, Heart Failure Research Centre, Academic Medical Center, Amsterdam, The Netherlands.|Department of Bioinformatics - BiGCaT, Maastricht University, Maastricht, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Adriaens
authors.affiliation: Department of Molecular Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD, Maastricht, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Voncken
authors.affiliation: Cancer Research UK Department of Oncology, The Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Harris
authors.affiliation: Cancer Research UK Department of Oncology, The Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada.
authors.forename: Syed
authors.initials: S
authors.lastname: Haider
authors.affiliation: Department of Radiation Oncology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD, Maastricht, The Netherlands.|Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada.
authors.forename: Maud H W
authors.initials: MHW
authors.lastname: Starmans
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.|Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada.
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Yao
authors.affiliation: Department of Medicine, The Indiana University Melvin and Bren Simon Cancer Center, Indianapolis 46202, USA.
authors.forename: Mircea
authors.initials: M
authors.lastname: Ivan
authors.affiliation: Center for RNA Interference and Non-Coding RNAs. The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Department of Thoracic, Head and Neck Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chad V
authors.initials: CV
authors.lastname: Pecot
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.|Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada.|Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.|Center for RNA Interference and Non-Coding RNAs. The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON M5G 2M9, Canada.|Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada.
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
authors.affiliation: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, ON M5G 2M9, Canada.|Department of Radiation Oncology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6200 MD, Maastricht, The Netherlands.|Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.|Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada.|Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada.
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism
chemical_list: C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases