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

• DOI: 10.1016/j.molcel.2015.05.036
• Publication Date: 2015-07-04T16:58:35Z
• Authors: Xin Zhang; Ramona Schulz; Shelley Edmunds; Elke Krüger; Elke Markert; Jochen Gaedcke; Estelle Cormet-Bo...; Michael Ghadimi; Tim Beissbarth; Arnold J. Levine; Ute M. Moll; Matthias Dobbelstein
• Keywords: 0301 basic medicine; Apoptosis; Breast Neoplasms; Bortezomib; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Molecular Biology; 3' Untranslated Regions; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor Proteins; Estrogen Receptor alpha; Cell Biology; Cell Cycle Checkpoints; Hep G2 Cells; HCT116 Cells; Boronic Acids; 3. Good health; MicroRNAs; Drug Resistance, Neoplasm; Gene Knockdown Techniques; MCF-7 Cells; Female

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 proteasome maturation protein POMP, leading to impaired assembly and activity, resulting in accumulation p53 cyclin-dependent kinase inhibitors, cell cycle arrest, apoptosis. miR-101-resistant POMP restores proper turnover substrates re-enables growth. In ERα-positive breast cancers, miR-101 levels are inversely correlated, high expression or low associates with prolonged survival. Mechanistically, knockdown attenuated estrogen-driven transcription. Finally, suppressing is sufficient overcome resistance inhibitor bortezomib. Taken together, activity can not only be manipulated through drugs, also subject endogenous regulation miR-101, which biogenesis control overall proliferation.