Hippo Signaling Suppresses Cell Ploidy and Tumorigenesis through Skp2

Abstract

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. Additionally, 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.

YAP promotes the proliferation of neuroblastoma cells through decreasing the nuclear location of p27Kip1 mediated by Akt

“…13 Consistent with these studies, our results showed that YAP was abundantly expressed in different glioma cell lines, and the expres- There are evidences revealing that YAP can modulate tumour cell proliferation through regulating the expression of cell cycle proteins, such as p27 Kip1 , p21 45 and cyclinD1. 25,28,43 p27 Kip1 is a cyclin-dependent kinases inhibitor that involved in the pathogenesis of neuroblastoma. Decreased transcription level of p27 Kip1 increases human susceptibility to neuroblastoma.…”

“…24 This means that low p27 kip1 level is conducive to cell proliferation, which is the widely accepted view. [25][26][27] However, there is also evidence showing that low p27 kip1 level can cause defect in cell cycle progression, and the expression of p27 kip1 can also be regulated by YAP. 28 The nuclear and cytoplasmic location of p27 kip1 might be the critical reason that affects cell proliferation, rather than the total p27 kip1 expression.…”

Ubiquitin ligases in oncogenic transformation and cancer therapy

“…Liverspecific loss of HIPPO signalling in a liver cancer mouse model also resulted in AKT–p300-mediated acetylation and cytoplasmic retention of SKP2 (REF. 92). In hepatocytes isolated from mouse strains with defective HIPPO signalling, cytoplasmic localization of SKP2 is associated with p27 KIP1 stabilization and, consequently, mitotic arrest and polyploidy 92 .…”

“…92). In hepatocytes isolated from mouse strains with defective HIPPO signalling, cytoplasmic localization of SKP2 is associated with p27 KIP1 stabilization and, consequently, mitotic arrest and polyploidy 92 . The effect of AKT activity on SKP2 is also linked to the degradation of the transcriptional activators forkhead box protein O1 (FOXO1) and FOXO3, which positively regulate apoptosis; in turn, this enables increased proliferation of polyploid cells, genomic instability and increased formation of HCC in the HIPPO signalling-deficient liver 92 .…”

Oxidized low‐density lipoprotein promotes vascular endothelial cell dysfunction by stimulating miR‐496 expression and inhibiting the Hippo pathway effector YAP

“…miRNAs have no open reading frame and do not encode a protein product with a specific function, but as single-stranded ncRNAs, they can reverse-complement with the mRNA transcripts of other genes to silence the target genes after transcription. In addition, YAP plays an important role in cell division and differentiation, stem cell fate decisions, and tumorigenesis and progression (Zhao et al, 2011;Xie et al, 2012;He et al, 2017;Li et al, 2017;Xiao et al, 2017;Zhang et al, 2017;Zhao et al, 2017;Zhuo and Kang, 2017). The Hippo-YAP/TAZ (Yesassociated protein/YLP motif-containing 1) pathway is a kinase cascade consisting of a series of protein kinases and transcription factors.…”