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Global microRNA expression analysis in HaCaT human keratinocytes transfected with p72 or control EGFP in addition to siRNAs for NF2 and LATS2.

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 post-transcriptional 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. Two conditions (transfection of p72 or control EGFP in addition to siRNAs for NF2 and LATS2) were analyzed in duplicate.

ORGANISM(S): Homo sapiens

SUBMITTER: Masaki Mori

PROVIDER: E-GEOD-52205 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Global microRNA expression analysis in HaCaT human keratinocytes at low and high cell densities

Project description: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 post-transcriptional 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. Two conditions (Low density and High density) were analyzed in duplicate.

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Global microRNA expression analysis in HaCaT human keratinocytes transfected with siRNA(s) for p72, NF2/LATS2, DROSHA/DGCR8, or negative control

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