Browsing by Author "van den Beucken, Twan"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression
    (Nature, 2020-06-03) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Medicine, School of Medicine
    This Article contains an error in Fig. 4. During the preparation of Fig. 4d, the image representing showing E-CADHERIN expression under hypoxia conditions in A2780 cells was inadvertently taken from the image in Supplementary Fig. 15C showing E-CADHERIN expression under hypoxia conditions in SKOV3 cells. The correct version of Fig. 4 is shown below. The error has not been corrected in the PDF or HTML versions of the Article.
  • Thumbnail Image
    Item
    Hypoxia Mediated Downregulation of miRNA Biogenesis Promotes Tumor Progression
    (Nature Publishing Group, 2014-10-29) Rupaimoole, Rajesha; Wu, Sherry Y.; Pradeep, Sunila; Ivan, Cristina; Pecot, Chad V.; Gharpure, Kshipra M.; Nagaraja, Archana S.; Armaiz-Pena, Guillermo N.; McGuire, Michael; Zand, Behrouz; Dalton, Heather J.; Filant, Justyna; Miller, Justin Bottsford; Lu, Chunhua; Sadaoui, Nouara C.; Mangala, Lingegowda S.; Taylor, Morgan; van den Beucken, Twan; Koch, Elizabeth; Rodriguez-Aguayo, Cristian; Huang, Li; Bar-Eli, Menashe; Wouters, Bradly G.; Radovich, Milan; Ivan, Mircea; Calin, George A.; Zhang, Wei; Lopez-Berestein, Gabriel; Sood, Anil K.; Department of Surgery, IU School of Medicine
    Cancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.
  • Thumbnail Image
    Item
    Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER
    (Nature Publishing Group, 2014-10-29) 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.; Department of Medicine, IU School of Medicine
    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 tumor 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 tumor stem cell phenotypes that may underlie poor outcome in breast cancer.