Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription
Cecilia Patitucci, … , Mario Pende, Ganna Panasyuk
Cecilia Patitucci, … , Mario Pende, Ganna Panasyuk
Published April 10, 2017
Citation Information: J Clin Invest. 2017;127(5):1873-1888. https://doi.org/10.1172/JCI90327.
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Research Article Hepatology Oncology

Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription

Abstract

Worldwide epidemics of metabolic diseases, including liver steatosis, are associated with an increased frequency of malignancies, showing the highest positive correlation for liver cancer. The heterogeneity of liver cancer represents a clinical challenge. In liver, the transcription factor PPARγ promotes metabolic adaptations of lipogenesis and aerobic glycolysis under the control of Akt2 activity, but the role of PPARγ in liver tumorigenesis is unknown. Here we have combined preclinical mouse models of liver cancer and genetic studies of a human liver biopsy atlas with the aim of identifying putative therapeutic targets in the context of liver steatosis and cancer. We have revealed a protumoral interaction of Akt2 signaling with hepatocyte nuclear factor 1α (HNF1α) and PPARγ, transcription factors that are master regulators of hepatocyte and adipocyte differentiation, respectively. Akt2 phosphorylates and inhibits HNF1α, thus relieving the suppression of hepatic PPARγ expression and promoting tumorigenesis. Finally, we observed that pharmacological inhibition of PPARγ is therapeutically effective in a preclinical murine model of steatosis-associated liver cancer. Taken together, our studies in humans and mice reveal that Akt2 controls hepatic tumorigenesis through crosstalk between HNF1α and PPARγ.

Authors

Cecilia Patitucci, Gabrielle Couchy, Alessia Bagattin, Tatiana Cañeque, Aurélien de Reyniès, Jean-Yves Scoazec, Raphaël Rodriguez, Marco Pontoglio, Jessica Zucman-Rossi, Mario Pende, Ganna Panasyuk

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Figure 5

HNF1α is a novel substrate of Akt2 phosphorylated on Ser247.

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HNF1α is a novel substrate of Akt2 phosphorylated on Ser247. (A) Immunob...
(A) Immunoblot analysis of endogenous HNF1α immunoprecipitated from liver tissue extracts of 5-month-old random-fed male mice of indicated genotypes with antibody recognizing an Akt-phosphorylation motif. The membrane was reprobed with anti-HNF1α antibody. Densitometric analysis of phosphorylated HNF1α normalized to immunoprecipitated HNF1α signals is presented. Data are means ± SEM, n = 4–5. *P < 0.05 vs. WT; #P < 0.05 vs. Pten LKO; 1-way ANOVA with Tukey’s multiple-comparisons test. (B) Immunoblot analysis of immunoprecipitated HNF1α-WT-MYC, HNF1α-S247A-MYC, and HNF1α-S247D-MYC proteins transiently overexpressed in HEK293T cells, using antibody recognizing an Akt-phosphorylation motif. The immunoblot with anti-HNF1α of the same membrane served as a loading control. (C) Immunoblot analysis of immunoprecipitated HNF1α-WT-MYC and HNF1α-S247A-MYC proteins transiently overexpressed in HEK293T cells, using antibody raised against phosphorylated S247HNF1α. (D and E) Immunoblot analysis of total protein extracts of immortalized WT mouse embryonic fibroblast cells transiently overexpressing Myc-tagged HNF1α WT protein. Twenty-four hours after transfection, cells were starved in Earle’s Balanced Salt Solution for 2 hours followed by 30 minutes of treatment with 100 nM Torin before stimulation with 10% FBS for 1 hour (D) or stimulation with 10% FBS for indicated times (E). (F) Immunoblot analysis of endogenous HNF1α immunoprecipitated from liver tissue extracts of 5-month-old random-fed male mice of indicated genotypes with antibody raised against phosphorylated S247HNF1α. Densitometric analysis of phosphorylated HNF1α normalized to total HNF1α is presented. Data are means ± SEM, n = 5. *P < 0.05 vs. WT; #P < 0.05 vs. Pten LKO; 1-way ANOVA with Tukey’s multiple-comparisons test. (G) Immunoblot analysis of nuclear protein extracts from livers of 3-month-old male mice with indicated antibodies. Densitometric analysis of lamin A/C–normalized signals is presented as a graph. Data are means ± SEM, n = 4. *P < 0.05 vs. WT; #P < 0.05 vs. Pten LKO mice; 2-tailed, unpaired Student’s t test.