[HTML][HTML] Hippo signaling regulates microprocessor and links cell-density-dependent miRNA biogenesis to cancer

M Mori, R Triboulet, M Mohseni, K Schlegelmilch… - Cell, 2014 - cell.com
M Mori, R Triboulet, M Mohseni, K Schlegelmilch, K Shrestha, FD Camargo, RI Gregory
Cell, 2014cell.com
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 …
Summary
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.
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