Summary: Polyploidy can lead to aneuploidy and tumorigenesis. 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 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. Importantly, the depletion or inactivation of Akt or Skp2 abrogated Hippo signal deficiency-induced liver tumorigenesis, indicating their epistatic interaction. Thus, we conclude that Hippo-Yap signaling suppresses cell polyploidy and oncogenesis through Skp2.

Significance: p53 is required for the induction of cell senescence to limit the proliferation of polyploid cells. We found that Hippo signal deficiency or Yap activation in mouse livers result in polyploid formation and polyploid cell growth. The combined loss of Hippo signals and p53 lead to greatly increased polyploidy and result in a higher incidence and earlier onset of liver tumors. We revealed that Yap induces cell polyploidy through the Skp2-mediated ubiquitin-proteasome pathway. Importantly, the deregulation of the Hippo-Yap-Skp2 axis is found in a substantial fraction of human hepatocellular carcinomas. Thus, Hippo-Yap signaling acts as an alternative polyploid checkpoint, together with p53, to synergistically restrain polyploid cell division, thus limiting the risk of genomic instability, aneuploidy, and tumorigenesis.

Link: http://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30159-9