Abstract IA09: The crosstalk between Hippo-YAP/TAZ and PTEN-AKT signaling in liver metabolic dysregulation and tumorigenesis

Several in vitro studies have suggested that Hippo-YAP/TAZ signaling regulates the AKT pathway components PI3K and PTEN. Increased YAP expression in human liver tumors is associated with high levels of phosphorylated AKT. This suggests that crosstalk between the Hippo and AKT pathways may be important in the maintenance of functional liver homeostasis. The nature of such crosstalk has thus far remained unclear. Here, we investigated the possible role of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in the liver. Deletion of both Pten and Sav1 in the liver (DKO) accelerates the development of nonalcoholic fatty liver disease (NAFLD) and liver cancer in mice through excessive activation of AKT. At the molecular level, activation of YAP and TAZ amplifies AKT signaling through direct upregulation of IRS2 expression. Deletion of YAP/TAZ or activation of Hippo attenuated development of fatty liver in these DKO mice by downregulating IRS2. Notably, increased YAP/TAZ expression was also associated with high level of IRS2-pAKT in the patient. Moreover, treatment with the AKT inhibitor MK-2206 attenuated NAFLD development and tumorigenesis in DKO mice. Our findings suggest that crosstalk between Hippo and AKT pathways at the level of YAP/TAZ-IRS2 contributes to the development and progression of NAFLD to liver cancer, and they therefore provide a basis for the development of new therapeutic interventions. Citation Format: Sun-Hye Jeong, Dae-Sik Lim. The crosstalk between Hippo-YAP/TAZ and PTEN-AKT signaling in liver metabolic dysregulation and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA09.