Hippo Signaling Regulates Microprocessor and Links Cell-Density-Dependent miRNA Biogenesis to Cancer
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, via la protéine YAP, la voie de signalisation Hippo régule la sous-expression de micro-ARNs dans les cellules tumorales en fonction de la densité cellulaire
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. "Hippo pathway regulates microRNA biogenesis "YAP sequesters p72 (DDX17) from the Microprocessor in a cell-density-dependent manner "p72 (DDX17) recognizes a sequence motif in pri-miRNAs "YAP mediates widespread microRNA suppression in tumors The Hippo-signaling pathway and its downstream target YAP regulate miRNA biogenesis in a cell-density-dependent manner, which may be responsible for the widespread miRNA repression commonly observed in human cancers.