Hippo Signaling Suppresses Cell Ploidy And Tumorigenesis Through Skp2

Polyploidy is a state in which cells possess more than two sets of homologous chromosomes.Polyploidy is a widespread physiological phenomenon observed particularly in plants,fungi,insects,fishes,and amphibians.Although most of the eukaryotic somatic cells are diploid,that is,only two groups of chromosomes,inherited from the male and female,respectively.Polyploid cells Centrosome overreplication and abnormally dividing can lead to aneuploidy,genomic instability and tumorigenesis.Previous study reported that p53 is required for the induction of cell senescence to limit the proliferation of polyploidy cells.Hippo pathway is activated in tetraploid cells,so we further studied the role of Hippo signaling pathway in the transformation between diploid cells and polyploid cells and tumor formation.Here we report that the Hippo pathway effector Yap promotes the diploid-polyploid conversion and polyploid cell growth through the Akt-Skp2 axis.Yap strongly induces the acetyltransferase p300-mediated acetylation of the E3 ligase Skp2 via Akt signaling.Acetylated Skp2 is exclusively localized in the cytosol,which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27,leading to cell mitotic arrest and subsequently cell polyploidy.Additionally,the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2,resulting in polyploid cell division,genomic instability and oncogenesis.Importantly,depletion or inactivation of Akt or Skp2 abrogated Hippo signal-deficiency-induced liver tumorigenesis,indicative of their epistatic interaction.At the same time,we also found a good correlation between tumorigenesis and Yap-AKT-Skp2 signaling pathway in clinical patient samples.Thus,we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.