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.
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Denmark.
authors.forename: Lisa B
authors.initials: LB
authors.lastname: Frankel
authors.forename: Jiayu
authors.initials: J
authors.lastname: Wen
authors.forename: Michael
authors.initials: M
authors.lastname: Lees
authors.forename: Maria
authors.initials: M
authors.lastname: Høyer-Hansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Farkas
authors.forename: Anders
authors.initials: A
authors.lastname: Krogh
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.forename: Anders H
authors.initials: AH
authors.lastname: Lund
mesh_terms: D001343:Autophagy; D000071183:Autophagy-Related Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering; D020123:Sirolimus / Q000494:pharmacology; D050777:Stathmin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000071183:Autophagy-Related Proteins; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C493995:STMN1 protein, human; D050777:Stathmin; D013629:Tamoxifen; C016601:afimoxifene; D005047:Etoposide; C543490:ATG4D protein, human; D003546:Cysteine Endopeptidases; D020696:rab5 GTP-Binding Proteins; D020123:Sirolimus