MicroRNA-101 Suppresses Tumor Cell Proliferation by Acting as an Endogenous Proteasome Inhibitor via Targeting the Proteasome Assembly Factor POMP

Xin Zhang; Ramona Schulz; Shelley Edmunds; Elke Krüger; Elke Markert; Jochen Gaedcke; Estelle Cormet-Boyaka; Michael Ghadimi; Tim Beissbarth; Arnold J Levine; Ute M Moll; Matthias Dobbelstein

doi:10.1016/j.molcel.2015.05.036

MicroRNA-101 Suppresses Tumor Cell Proliferation by Acting as an Endogenous Proteasome Inhibitor via Targeting the Proteasome Assembly Factor POMP

Mol Cell. 2015 Jul 16;59(2):243-57. doi: 10.1016/j.molcel.2015.05.036. Epub 2015 Jul 2.

Authors

Affiliations

¹ Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany.
² Institut für Biochemie, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
³ Cancer Research UK Beatson Institute, Glasgow, G61 1BD Scotland, UK.
⁴ Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
⁵ Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
⁶ Department of Medical Statistics, University Medical Center Göttingen, 37075 Göttingen, Germany.
⁷ Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540, USA.
⁸ Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
⁹ Institute of Molecular Oncology, University Medical Center Göttingen, 37077 Göttingen, Germany. Electronic address: mdobbel@gwdg.de.

PMID: 26145175
DOI: 10.1016/j.molcel.2015.05.036

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Apoptosis
Boronic Acids / pharmacology
Bortezomib
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor Proteins / metabolism
Drug Resistance, Neoplasm / genetics
Estrogen Receptor alpha / metabolism
Female
Gene Knockdown Techniques
HCT116 Cells
Hep G2 Cells
Humans
MCF-7 Cells
Mice
MicroRNAs / genetics*
MicroRNAs / metabolism*
Molecular Chaperones / antagonists & inhibitors
Molecular Chaperones / genetics*
Molecular Chaperones / metabolism*
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / metabolism*
Proteasome Inhibitors / pharmacology
Pyrazines / pharmacology
RNA, Small Interfering / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

3' Untranslated Regions
Boronic Acids
Cyclin-Dependent Kinase Inhibitor Proteins
ESR1 protein, human
Estrogen Receptor alpha
MIRN101 microRNA, human
MicroRNAs
Molecular Chaperones
Proteasome Inhibitors
Pyrazines
RNA, Small Interfering
TP53 protein, human
Tumor Suppressor Protein p53
proteasome maturation protein
Bortezomib
Proteasome Endopeptidase Complex

Associated data

GEO/GSE69150