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.

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Summary The transcriptional co-activator YAP plays an important role in organ size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced GSH depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects acetaminophen-induced liver injury. Similar to its effects on YAP, the Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP.

Highlights d FGF15 activates Mst1/2 through hepatic FGFR4 in response to increased bile acids d NF2 switches FGFR4's role from pro-oncogenic to anti-tumor signaling via Mst1/2 d Mst1/2 acts as a key negative feedback suppressor of bile acid synthesis via SHP d Depletion of bile acids retards Mst1/2-mutant-driven liver growth and oncogenesis

Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment. The effects of CAFs on the progression of colorectal cancer (CRC) remain controversial. In this study, we found the ectopic overexpression of Fibronectin leucine-rich transmembrane protein 3 (FLRT3) inhibited the process of Epithelial-mesenchymal transition (EMT), as well as the proliferation, migration, invasion, and promote apoptosis of CRC cells, whereas silencing FLRT3 expression resulted in the opposite phenomenon. FLRT3 downregulation was associated with a poor prognosis in CRC. Also, FLRT3 expression was significantly related to some clinicopathological factors, including T stage (p=0.037), N stage (p=0.042), and E-cadherin (p=0.002) level. Via univariate and multivariate analyses, M stage (p<0.0001), FLRT3 (p=0.044), and E-cadherin (p=0.003) were associated with overall survival and were independent prognostic factors for it. Mechanistically, CAFs secreted TGF-β, which downregulated FLRT3 expression by activating SMAD4 to promote aggressive phenotypes in CRC cells. Moreover, FLRT3 repressed tumorigenesis and lung metastasis, which could be reversed by LY2109761, a dual inhibitor of TGF-β receptor type I and II. Treatment with LY2109761 increased IFN-γ expression in CD8+ T cells and reduced the number of regulatory T cells in the tumor microenvironment. Taken together, we revealed the metastasis-suppressive function of FLRT3, which was attenuated during the CAFs-mediated activation of the TGF-β/SMAD4 signaling pathway to promote EMT in CRC. LY2109761 that significantly inhibited metastasis could be a new treatment option for advanced CRC. Implications: CAFs enhance CRC aggressiveness by reducing FLRT3 expression through activating TGF-β/SMAD4 signaling pathway. CAFs-targeted therapy and/or LY2109761 were promising treatments for CRC.