Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

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 tumour...

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Bibliographic Details
Published in:Nature communications Vol. 5; no. 1; p. 5202
Main Authors: 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.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 29.10.2014
Nature Publishing Group
Subjects:
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13/89
14/1
14/5
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631/67
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Animals
Biosynthesis
Cancer
Cell Hypoxia - genetics
Cell Line, Tumor
DEAD-box RNA Helicases - genetics
DEAD-box RNA Helicases - metabolism
Deregulation
Disease Progression
Down-Regulation - genetics
Epithelial-Mesenchymal Transition - genetics
Ets-1 protein
Female
Gene expression
Gene Expression Regulation, Neoplastic
Gene regulation
Homeostasis
Humanities and Social Sciences
Humans
Hypoxia
Maturation
Mice, Nude
MicroRNAs
MicroRNAs - biosynthesis
MicroRNAs - genetics
miRNA
Models, Biological
multidisciplinary
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - pathology
Post-transcription
Proto-Oncogene Protein c-ets-1 - genetics
Proto-Oncogene Protein c-ets-1 - metabolism
Ribonuclease III - genetics
Ribonuclease III - metabolism
Ribonucleic acid
RNA
Science
siRNA
Transcription factors
Tumor microenvironment
Tumors
Vascular Endothelial Growth Factor A - antagonists & inhibitors
Vascular Endothelial Growth Factor A - metabolism
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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 tumour 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 tumours. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumour regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumour microenvironment. MicroRNAs play important roles in the maintenance of cellular homeostasis through the post-transcriptional regulation of gene expression. Here, the authors implicate loss of the miRNA biogenesis factor Drosha and altered miRNA maturation in tumour progression under hypoxic conditions.
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ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms6202