Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Rajesha Rupaimoole; Sherry Y. Wu; Sunila Pradeep; Cristina Ivan; Chad V. Pecot; Kshipra M. Gharpure; Archana S. Nagaraja; Guillermo N. Armaiz-Pena; Michael McGuire; Behrouz Zand; Heather J. Dalton; Justyna Filant; Justin Bottsford Miller; Chunhua Lu; Nouara C. Sadaoui; Lingegowda S. Mangala; Morgan Taylor; Twan Van Den Beucken; Elizabeth Koch; Cristian Rodriguez-Aguayo; Li Huang; Menashe Bar-Eli; Bradly G. Wouters; Milan Radovich; Mircea Ivan; George A. Calin; Wei Zhang; Gabriel Lopez-Berestein; Anil K. Sood

doi:10.1038/ncomms6202

Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Rajesha Rupaimoole, Sherry Y. Wu, Sunila Pradeep, Cristina Ivan, Chad V. Pecot, Kshipra M. Gharpure, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, Michael McGuire, Behrouz Zand, Heather J. Dalton, Justyna Filant, Justin Bottsford Miller, Chunhua Lu, Nouara C. Sadaoui, Lingegowda S. Mangala, Morgan Taylor, Twan Van Den Beucken, Elizabeth Koch, Cristian Rodriguez-AguayoLi Huang, Menashe Bar-Eli, Bradly G. Wouters, Milan Radovich, Mircea Ivan, George A. Calin, Wei Zhang, Gabriel Lopez-Berestein, Anil K. Sood

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Abstract

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.

Original language	English (US)
Article number	5202
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6202
State	Published - Feb 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Rupaimoole, R., Wu, S. Y., Pradeep, S., Ivan, C., Pecot, C. V., Gharpure, K. M., Nagaraja, A. S., Armaiz-Pena, G. N., McGuire, M., Zand, B., Dalton, H. J., Filant, J., Miller, J. B., Lu, C., Sadaoui, N. C., Mangala, L. S., Taylor, M., Van Den Beucken, T., Koch, E., ... Sood, A. K. (2015). Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression. Nature communications, 5, Article 5202. https://doi.org/10.1038/ncomms6202

Rupaimoole, R, Wu, SY, Pradeep, S, Ivan, C, Pecot, CV, Gharpure, KM, Nagaraja, AS, Armaiz-Pena, GN, McGuire, M, Zand, B, Dalton, HJ, Filant, J, Miller, JB, Lu, C, Sadaoui, NC, Mangala, LS, Taylor, M, Van Den Beucken, T, Koch, E, Rodriguez-Aguayo, C, Huang, L, Bar-Eli, M, Wouters, BG, Radovich, M, Ivan, M, Calin, GA, Zhang, W, Lopez-Berestein, G & Sood, AK 2015, 'Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression', Nature communications, vol. 5, 5202. https://doi.org/10.1038/ncomms6202

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title = "Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression",

abstract = "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.",

author = "Rajesha Rupaimoole and Wu, {Sherry Y.} and Sunila Pradeep and Cristina Ivan and Pecot, {Chad V.} and Gharpure, {Kshipra M.} and Nagaraja, {Archana S.} and Armaiz-Pena, {Guillermo N.} and Michael McGuire and Behrouz Zand and Dalton, {Heather J.} and Justyna Filant and Miller, {Justin Bottsford} and Chunhua Lu and Sadaoui, {Nouara C.} and Mangala, {Lingegowda S.} and Morgan Taylor and {Van Den Beucken}, Twan and Elizabeth Koch and Cristian Rodriguez-Aguayo and Li Huang and Menashe Bar-Eli and Wouters, {Bradly G.} and Milan Radovich and Mircea Ivan and Calin, {George A.} and Wei Zhang and Gabriel Lopez-Berestein and Sood, {Anil K.}",

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doi = "10.1038/ncomms6202",

language = "English (US)",

volume = "5",

journal = "Nature communications",

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T1 - Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

AU - Rupaimoole, Rajesha

AU - Wu, Sherry Y.

AU - Pradeep, Sunila

AU - Ivan, Cristina

AU - Pecot, Chad V.

AU - Gharpure, Kshipra M.

AU - Nagaraja, Archana S.

AU - Armaiz-Pena, Guillermo N.

AU - McGuire, Michael

AU - Zand, Behrouz

AU - Dalton, Heather J.

AU - Filant, Justyna

AU - Miller, Justin Bottsford

AU - Lu, Chunhua

AU - Sadaoui, Nouara C.

AU - Mangala, Lingegowda S.

AU - Taylor, Morgan

AU - Van Den Beucken, Twan

AU - Koch, Elizabeth

AU - Rodriguez-Aguayo, Cristian

AU - Huang, Li

AU - Bar-Eli, Menashe

AU - Wouters, Bradly G.

AU - Radovich, Milan

AU - Ivan, Mircea

AU - Calin, George A.

AU - Zhang, Wei

AU - Lopez-Berestein, Gabriel

AU - Sood, Anil K.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

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Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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