LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer
- Pan Xu1,
- Maaike H. Oosterveer2,6,
- Sokrates Stein1,6,
- Hadrien Demagny1,
- Dongryeol Ryu3,
- Norman Moullan1,3,
- Xu Wang3,
- Emine Can4,
- Nicola Zamboni5,
- Arnaud Comment4,
- Johan Auwerx3 and
- Kristina Schoonjans1
- 1Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
- 2Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, NL-9700 RB Groningen, The Netherlands;
- 3Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
- 4Institute of the Physics of Biological Systems, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
- 5Department of Biology, Institute for Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zurich, Switzerland
- Corresponding author: kristina.schoonjans{at}epfl.ch
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↵6 These authors contributed equally to this work.
Abstract
Various tumors develop addiction to glutamine to support uncontrolled cell proliferation. Here we identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. In particular, we show that gain and loss of function of hepatic LRH-1 modulate the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of this pathway. Acute and chronic deletion of hepatic LRH-1 blunts the deamination of glutamine and reduces glutamine-dependent anaplerosis. The robust reduction in glutaminolysis and the limiting availability of α-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamine-induced metabolism and signaling to promote hepatocellular carcinogenesis.
Keywords
- Hepatocellular carcinoma
- cancer metabolism
- nuclear receptor NR5A2
- mitochondria
- anaplerosis
- mTOR
- NADPH
Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.277483.116.
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Freely available online through the Genes & Development Open Access option.
- Received January 7, 2016.
- Accepted May 12, 2016.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.