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

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

Author information

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.

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.

PMID:
26145175
DOI:
10.1016/j.molcel.2015.05.036
[Indexed for MEDLINE]
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