title: Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer.
abstract: Global downregulation of microRNAs (miRNAs) is commonly observed in human cancers and can have a causative role in tumorigenesis. The mechanisms responsible for this phenomenon remain poorly understood. Here, we show that YAP, the downstream target of the tumor-suppressive Hippo-signaling pathway regulates miRNA biogenesis in a cell-density-dependent manner. At low cell density, nuclear YAP binds and sequesters p72 (DDX17), a regulatory component of the miRNA-processing machinery. At high cell density, Hippo-mediated cytoplasmic retention of YAP facilitates p72 association with Microprocessor and binding to a specific sequence motif in pri-miRNAs. Inactivation of the Hippo pathway or expression of constitutively active YAP causes widespread miRNA suppression in cells and tumors and a corresponding posttranscriptional induction of MYC expression. Thus, the Hippo pathway links contact-inhibition regulation to miRNA biogenesis and may be responsible for the widespread miRNA repression observed in cancer.
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Robinson
authors.initials: R
authors.lastname: Triboulet
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Morvarid
authors.initials: M
authors.lastname: Mohseni
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Schlegelmilch
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA.
authors.forename: Kriti
authors.initials: K
authors.lastname: Shrestha
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: fernando.camargo@childrens.harvard.edu.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Camargo
authors.affiliation: Stem Cell Program, Boston Children's Hospital, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Boston, MA 02115, USA. Electronic address: rgregory@enders.tch.harvard.edu.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
mesh_terms: D002452:Cell Count; D018797:Cell Cycle Proteins; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
chemical_list: D018797:Cell Cycle Proteins; C489427:MYC protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D017346:Protein Serine-Threonine Kinases; C102004:DDX17 protein, human; D053487:DEAD-box RNA Helicases