microRNA-101 is a potent inhibitor of autophagy

Lisa B Frankel; Jiayu Wen; Michael Lees; Maria Høyer-Hansen; Thomas Farkas; Anders Krogh; Marja Jäättelä; Anders H Lund

doi:10.1038/emboj.2011.331

microRNA-101 is a potent inhibitor of autophagy

Lisa B Frankel, Jiayu Wen, Michael Lees, Maria Høyer-Hansen, Thomas Farkas, Anders Krogh, Marja Jäättelä, Anders H Lund

Computational and RNA Biology

266 Citations (Scopus)

Abstract

Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer. To further elucidate regulatory mechanisms of autophagy, we performed a functional screen in search of microRNAs (miRNAs), which regulate the autophagic flux in breast cancer cells. In this study, we identified the tumour suppressive miRNA, miR-101, as a potent inhibitor of basal, etoposide- and rapamycin-induced autophagy. Through transcriptome profiling, we identified three novel miR-101 targets, STMN1, RAB5A and ATG4D. siRNA-mediated depletion of these genes phenocopied the effect of miR-101 overexpression, demonstrating their importance in autophagy regulation. Importantly, overexpression of STMN1 could partially rescue cells from miR-101-mediated inhibition of autophagy, indicating a functional importance for this target. Finally, we show that miR-101-mediated inhibition of autophagy can sensitize breast cancer cells to 4-hydroxytamoxifen (4-OHT)-mediated cell death. Collectively, these data establish a novel link between two highly important and rapidly growing research fields and present a new role for miR-101 as a key regulator of autophagy.

Original language	English
Journal	E M B O Journal
Volume	30
Pages (from-to)	4628-4641
Number of pages	14
ISSN	0261-4189
DOIs	https://doi.org/10.1038/emboj.2011.331
Publication status	Published - 16 Nov 2011

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title = "microRNA-101 is a potent inhibitor of autophagy",

abstract = "Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer. To further elucidate regulatory mechanisms of autophagy, we performed a functional screen in search of microRNAs (miRNAs), which regulate the autophagic flux in breast cancer cells. In this study, we identified the tumour suppressive miRNA, miR-101, as a potent inhibitor of basal, etoposide- and rapamycin-induced autophagy. Through transcriptome profiling, we identified three novel miR-101 targets, STMN1, RAB5A and ATG4D. siRNA-mediated depletion of these genes phenocopied the effect of miR-101 overexpression, demonstrating their importance in autophagy regulation. Importantly, overexpression of STMN1 could partially rescue cells from miR-101-mediated inhibition of autophagy, indicating a functional importance for this target. Finally, we show that miR-101-mediated inhibition of autophagy can sensitize breast cancer cells to 4-hydroxytamoxifen (4-OHT)-mediated cell death. Collectively, these data establish a novel link between two highly important and rapidly growing research fields and present a new role for miR-101 as a key regulator of autophagy.",

author = "Frankel, {Lisa B} and Jiayu Wen and Michael Lees and Maria H{\o}yer-Hansen and Thomas Farkas and Anders Krogh and Marja J{\"a}{\"a}ttel{\"a} and Lund, {Anders H}",

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language = "English",

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T1 - microRNA-101 is a potent inhibitor of autophagy

AU - Frankel, Lisa B

AU - Wen, Jiayu

AU - Lees, Michael

AU - Høyer-Hansen, Maria

AU - Farkas, Thomas

AU - Krogh, Anders

AU - Jäättelä, Marja

AU - Lund, Anders H

PY - 2011/11/16

Y1 - 2011/11/16

N2 - Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer. To further elucidate regulatory mechanisms of autophagy, we performed a functional screen in search of microRNAs (miRNAs), which regulate the autophagic flux in breast cancer cells. In this study, we identified the tumour suppressive miRNA, miR-101, as a potent inhibitor of basal, etoposide- and rapamycin-induced autophagy. Through transcriptome profiling, we identified three novel miR-101 targets, STMN1, RAB5A and ATG4D. siRNA-mediated depletion of these genes phenocopied the effect of miR-101 overexpression, demonstrating their importance in autophagy regulation. Importantly, overexpression of STMN1 could partially rescue cells from miR-101-mediated inhibition of autophagy, indicating a functional importance for this target. Finally, we show that miR-101-mediated inhibition of autophagy can sensitize breast cancer cells to 4-hydroxytamoxifen (4-OHT)-mediated cell death. Collectively, these data establish a novel link between two highly important and rapidly growing research fields and present a new role for miR-101 as a key regulator of autophagy.

AB - Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer. To further elucidate regulatory mechanisms of autophagy, we performed a functional screen in search of microRNAs (miRNAs), which regulate the autophagic flux in breast cancer cells. In this study, we identified the tumour suppressive miRNA, miR-101, as a potent inhibitor of basal, etoposide- and rapamycin-induced autophagy. Through transcriptome profiling, we identified three novel miR-101 targets, STMN1, RAB5A and ATG4D. siRNA-mediated depletion of these genes phenocopied the effect of miR-101 overexpression, demonstrating their importance in autophagy regulation. Importantly, overexpression of STMN1 could partially rescue cells from miR-101-mediated inhibition of autophagy, indicating a functional importance for this target. Finally, we show that miR-101-mediated inhibition of autophagy can sensitize breast cancer cells to 4-hydroxytamoxifen (4-OHT)-mediated cell death. Collectively, these data establish a novel link between two highly important and rapidly growing research fields and present a new role for miR-101 as a key regulator of autophagy.

U2 - 10.1038/emboj.2011.331

DO - 10.1038/emboj.2011.331

M3 - Journal article

C2 - 21915098

SN - 0261-4189

VL - 30

SP - 4628

EP - 4641

JO - E M B O Journal

JF - E M B O Journal

ER -

microRNA-101 is a potent inhibitor of autophagy

Abstract

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