Hippo Signaling Suppresses Cell Ploidy And Tumorigenesis Through AKT-Skp2-FoxO1/3 Axis

Polyploidy is a state in which cells possess more than two sets of homologous chromosomes.Although most of the eukaryotic somatic cells are diploid,Liver tissue have a high percentage of polyploid cells.Liver is one of the important organs that remove toxic metabolite,while which is easy to induce gene mutation.Polyploid is considered to provide compensatory normal gene to maintain liver homeostasis.However,Polyploidy can lead to genomic instability,aneuploidy,and tumorigenesis when they do not arrest in G1 phase of cell cycle.Previous study reported that p53 is required for the induction of cell senescence to limit the proliferation of polyploidy cells.Hippo signaling pathway is a critical regulator of tissue regeneration,and organ size,which is highly actived in polyploid cells,and overexpression of its downstream effector YAP increases hepatocyte polyploidy.Thus,it is necessary to determine the mechanisms regulating polyploid formation and polyploidy cell division for understanding the pathogenesis of liver cancer and liver cancer treatment.Here we found that YAP activation in response to loss of Hippo signaling promoted hepatocyte polyploidy in mice and synergized with p53 inactivation to induce liver tumorigenesis.Hippo signal deficiency or Yap activation turn on AKT signaling,thereby activating the acetyltransferase p300 to promote the E3 ligase Skp2 acetylation.Acetylated Skp2 is exclusively localized to the cytosol,which causes hyper-accumulation of the cyclin-dependent kinase inhibitor p27,leading to mitotic arrest and subsequently cell polyploidy.In addition,the pro-apoptotic factors FoxO1/3 are overly degraded by acetylated Skp2,resulting in polyploid cell division,genomic instability and oncogenesis.Moreover,inhibition of Akt or p27 reduces,whereas the depletion of Skp2 has no significant effect on cell polyploidy,but does prevent polyploid cell division and abrogates liver overgrowth and tumorigenesis.These data indicate that Hippo-Skp2 signaling maintaining Skp2-mediated p27 degradation in the nuclei to limit polyploidy formation and preventing Skp2-mediated FoxO1/3 degradation in the cytosol to block polyploidy cell division,thereby limiting the risk of genomic instability,aneuploidy,and tumorigenesis.Thus,we conclude that Hippo signaling suppresses cell ploidy and tumorigenesis through AKT-Skp2-FoxO1/3 axis.