Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer
Sun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, Dae-Sik Lim
Sun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, Dae-Sik Lim
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Research Article Hepatology Metabolism

Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major risk factor for liver cancer; therefore, its prevention is an important clinical goal. Ablation of phosphatase and tensin homolog (PTEN) or the protein kinase Hippo signaling pathway induces liver cancer via activation of AKT or the transcriptional regulators YAP/TAZ, respectively; however, the potential for crosstalk between the PTEN/AKT and Hippo/YAP/TAZ pathways in liver tumorigenesis has thus far remained unclear. Here, we have shown that deletion of both PTEN and SAV1 in the liver accelerates the development of NAFLD and liver cancer in mice. At the molecular level, activation of YAP/TAZ in the liver of Pten–/– Sav1–/– mice amplified AKT signaling through the upregulation of insulin receptor substrate 2 (IRS2) expression. Both ablation of YAP/TAZ and activation of the Hippo pathway could rescue these phenotypes. A high level of YAP/ TAZ expression was associated with a high level of IRS2 expression in human hepatocellular carcinoma (HCC). Moreover, treatment with the AKT inhibitor MK-2206 or knockout of IRS2 by AAV-Cas9 successfully repressed liver tumorigenesis in Pten–/– Sav1–/– mice. Thus, our findings suggest that Hippo signaling interacts with AKT signaling by regulating IRS2 expression to prevent NAFLD and liver cancer progression and provide evidence that impaired crosstalk between these 2 pathways accelerates NAFLD and liver cancer.

Authors

Sun-Hye Jeong, Han-Byul Kim, Min-Chul Kim, Ji-min Lee, Jae Ho Lee, Jeong-Hwan Kim, Jin-Woo Kim, Woong-Yang Park, Seon-Young Kim, Jae Bum Kim, Haeryoung Kim, Jin-Man Kim, Hueng-Sik Choi, Dae-Sik Lim

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Figure 4

YAP/TAZ directly activate Irs2 transcription through TEAD binding.

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YAP/TAZ directly activate Irs2 transcription through TEAD binding. (A) I...
(A) Immunoblot analyses of insulin signaling molecules in the livers of 3-month-old mice. (B) qPCR analysis of Irs2 mRNA levels in the same livers as in A. (C–G) Representative immunoblot analyses of AML12 cells infected with lentiviruses encoding shPten and/or shSav1 (C)and their insulin-induced AKT activity (D). AML12 cells were infected with a retrovirus encoding IRS2 or a control (CTL) (E), and shPten- and shSav1-expressing AML12 cells in C were transfected with siIrs2 or control (siCtl) (F). AML12 cells were infected with retrovirus encoding TAZ4SA or TAZ4SA/S51A (G). In D and F, the cells were deprived of serum for 16 hours and then treated with insulin (100 nM) for the indicated durations. (H and I) Luciferase reporter assay (I) for 293T cells expressing TAZ4SA or TAZ4SA/S51A as well as luciferase (Luc) reporter constructs that include regions of the Irs2 distal promoter and first intron (H) containing WT or deleted (TBSsΔ). Ex, exon. (J) ChIP-qPCR analysis of the binding of TAZ to the Irs2 promoter analyzed in I. AML12 cells infected with control or TAZ4SA retroviruses and subjected to immunoprecipitation with antibodies recognizing TAZ or IgG. Quantitative data in B, I, and J represent the mean ± SEM. **P < 0.01 and ***P < 0.001 versus the corresponding CTL; †P < 0.05, ††P < 0.01, and †††P < 0.001 for the indicated comparisons. One-way ANOVA (B) and Student’s t test (I and J). (A and B) n = 3 for each group. (C–J) n = 3 independent experiments; (I) n = 5 independent experiments.