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

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. [Display omitted] •miR-101 functions as an endogenous proteasome inhibitor by targeting POMP•Targeting POMP is essential for cell growth suppression by miR-101•High miR-101 levels have good outcomes for ERα-positive breast cancer patients•Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib The proteasome represents a cancer drug target, and its inhibition results in the accumulation of tumor-suppressive proteins. Zhang et al. identify a microRNA that targets the proteasome maturation factor POMP and interferes with proteasome assembly. It thus serves as an endogenous proteasome antagonist and a suppressor of cancer cell survival.