Abstract

Activation of the Hippo pathway effector Yap underlies many liver cancers, however no germline or somatic mutations have been identified. Autophagy maintains essential metabolic functions of the liver, and autophagy-deficient murine models develop benign adenomas and hepatomegaly, which have been attributed to activation of the p62/Sqstm1-Nrf2 axis. Here, we show that Yap is an autophagy substrate and mediator of tissue remodeling and hepatocarcinogenesis independent of the p62/Sqstm1-Nrf2 axis. Hepatocyte-specific deletion of Atg7 promotes liver size, fibrosis, progenitor cell expansion, and hepatocarcinogenesis, which is rescued by concurrent deletion of Yap. Our results shed new light on mechanisms of Yap degradation and the sequence of events that follow disruption of autophagy, which is impaired in chronic liver disease.

Details

Title
Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap
Author
Lee, Youngmin A 1 ; Noon, Luke A 2 ; Akat, Kemal M 3 ; Ybanez, Maria D 4 ; Ting-Fang, Lee 4 ; Berres, Marie-Luise 5 ; Fujiwara, Naoto 6 ; Goossens, Nicolas 7 ; Chou, Hsin-I 4 ; Parvin-Nejad, Fatemeh P 4 ; Khambu, Bilon 8 ; Kramer, Elisabeth G M 9 ; Gordon, Ronald 10 ; Pfleger, Cathie 11 ; Germain, Doris 12 ; John, Gareth R 9 ; Campbell, Kirk N 13 ; Yue, Zhenyu 9 ; Xiao-Ming, Yin 8 ; Cuervo, Ana Maria 14   VIAFID ORCID Logo  ; Czaja, Mark J 15 ; Fiel, M Isabel 10 ; Hoshida, Yujin 6   VIAFID ORCID Logo  ; Friedman, Scott L 4   VIAFID ORCID Logo 

1  Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, USA 
2  Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; CIBERDEM, Centro de Investigación Príncipe Felipe, Valencia, Spain 
3  Laboratory of RNA Molecular Biology, Rockefeller University, New York, NY, USA 
4  Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
5  Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
6  Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA 
7  Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland 
8  Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA 
9  Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
10  Department for Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
11  Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
12  Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 
13  Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, USA 
14  Department of Developmental and Molecular Biology, Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA 
15  Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA 
Pages
1-12
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-07338-z
ProQuest document ID
2137122160
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.