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 W Voncken; Adrian L Harris; Francesca M Buffa; Syed Haider; Maud H Starmans; Cindy Q Yao; Mircea Ivan; Cristina Ivan; Chad V Pecot; Paul C Boutros; Anil K Sood; Marianne Koritzinsky; Bradly G Wouters

doi:10.1038/ncomms6203

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 W Voncken, Adrian L Harris, Francesca M Buffa, Syed Haider, Maud H Starmans, Cindy Q Yao, Mircea Ivan, Cristina Ivan, Chad V Pecot, Paul C Boutros, Anil K Sood, Marianne Koritzinsky, Bradly G Wouters^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Pages (from-to)	5203
Number of pages	1
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6203
Publication status	Published - 2014

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10.1038/ncomms6203

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van den Beucken, T., Koch, E., Chu, K., Rupaimoole, R., Prickaerts, P., Adriaens, M., Voncken, J. W., Harris, A. L., Buffa, F. M., Haider, S., Starmans, M. H., Yao, C. Q., Ivan, M., Ivan, C., Pecot, C. V., Boutros, P. C., Sood, A. K., Koritzinsky, 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

@article{3e0b9cc75ab740ef82e514952dc820e8,

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 W} and Harris, {Adrian L} and Buffa, {Francesca M} and Syed Haider and Starmans, {Maud H} 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 = "10.1038/ncomms6203",

year = "2014",

doi = "10.1038/ncomms6203",

language = "English",

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pages = "5203",

journal = "Nature Communications",

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van den Beucken, T, Koch, E, Chu, K, Rupaimoole, R, Prickaerts, P, Adriaens, M, Voncken, JW, Harris, AL, Buffa, FM, Haider, S, Starmans, MH, 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, pp. 5203. https://doi.org/10.1038/ncomms6203

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T1 - Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER.

AU - van den Beucken, Twan

AU - Koch, Elizabeth

AU - Chu, Kenneth

AU - Rupaimoole, Rajesha

AU - Prickaerts, Peggy

AU - Adriaens, Michiel

AU - Voncken, Jan W

AU - Harris, Adrian L

AU - Buffa, Francesca M

AU - Haider, Syed

AU - Starmans, Maud H

AU - Yao, Cindy Q

AU - Ivan, Mircea

AU - Ivan, Cristina

AU - Pecot, Chad V

AU - Boutros, Paul C

AU - Sood, Anil K

AU - Koritzinsky, Marianne

AU - Wouters, Bradly G

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PY - 2014

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N2 - 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.

AB - 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.

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DO - 10.1038/ncomms6203

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