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.


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


  • 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