Sequential cleavage of long primary microRNAs (pri-miRNAs) by the Microprocessor (also known as DROSHA) and Dicer protein complexes generates ~22–base pair miRNAs that bind to and regulate the stability of messenger RNAs. Several cancers have decreased abundance of miRNAs. Some tumors show loss of cell-contact inhibition, a phenomenon associated with high cell density, and the abundance of many miRNAs is increased by high cell density. Cell-contact inhibition decreases the activation of the tumor-suppressive Hippo pathway and promotes the cytoplasmic retention of Yes-associated protein 1 (YAP), a transcriptional coactivator. Mori et al. found that YAP was responsible for the cell density–dependent conversion of pri-miRNAs to miRNAs. Culturing untransformed cells at high density increased the activity of the Microprocessor complex, an effect that was reversed by inhibiting proteins that promote the cytoplasmic retention of YAP or by overexpressing YAP. In cells grown at low density, YAP coimmunoprecipitated with p72, a component of the Microprocessor complex. In low-density cells or cells overexpressing nuclear-targeted YAP, YAP binding sequestered p72 away from other members of the Microprocessor complex. Global miRNA profiling revealed that nuclear YAP repressed 61% of miRNAs, 49% of which were also repressed by p72 knockdown and low-density cell culture. The latter group included let-7 and miR-34a, which target the RNA of the oncogene MYC. Culturing cells at low density or overexpression of nuclear YAP, or forms of YAP that cannot activate transcription, activated a luciferase-based reporter of MYC degradation. In malignant cells of Hippo-YAP–based mouse models of squamous cell and hepatic cancers, the abundance of several miRNAs was decreased and that of pri-miRNAs was increased. Thus, in cells at low cell density and in tumor cells, YAP inhibits miRNA biogenesis by a transcriptionally independent mechanism and may thereby contribute to oncogenic progression.
M. Mori, R. Triboulet, M. Mohseni, K. Schlegelmilch, K. Shrestha, F. D. Camargo, R. I. Gregory, Hippo signaling regulates Microprocessor and links cell-density-dependent miRNA biogenesis to cancer. Cell 156, 893–906 (2014). [PubMed]