title: MicroRNA-101 Suppresses Tumor Cell Proliferation by Acting as an Endogenous Proteasome Inhibitor via Targeting the Proteasome Assembly Factor POMP.
abstract: Proteasome inhibition represents a promising strategy of cancer pharmacotherapy, but resistant tumor cells often emerge. Here we show that the microRNA-101 (miR-101) targets the proteasome maturation protein POMP, leading to impaired proteasome assembly and activity, and resulting in accumulation of p53 and cyclin-dependent kinase inhibitors, cell cycle arrest, and apoptosis. miR-101-resistant POMP restores proper turnover of proteasome substrates and re-enables tumor cell growth. In ERα-positive breast cancers, miR-101 and POMP levels are inversely correlated, and high miR-101 expression or low POMP expression associates with prolonged survival. Mechanistically, miR-101 expression or POMP knockdown attenuated estrogen-driven transcription. Finally, suppressing POMP is sufficient to overcome tumor cell resistance to the proteasome inhibitor bortezomib. Taken together, proteasome activity can not only be manipulated through drugs, but is also subject to endogenous regulation through miR-101, which targets proteasome biogenesis to control overall protein turnover and tumor cell proliferation.
authors.affiliation: Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Schulz
authors.affiliation: Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany.
authors.forename: Shelley
authors.initials: S
authors.lastname: Edmunds
authors.affiliation: Institut für Biochemie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Krüger
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, G61 1BD Scotland, UK.
authors.forename: Elke
authors.initials: E
authors.lastname: Markert
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Estelle
authors.initials: E
authors.lastname: Cormet-Boyaka
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ghadimi
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, 37075 Göttingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.affiliation: Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Ute M
authors.initials: UM
authors.lastname: Moll
authors.affiliation: Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany. Electronic address: mdobbel@gwdg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Dobbelstein
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D001897:Boronic Acids; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; D018832:Molecular Chaperones; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C110856:proteasome maturation protein; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex