LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer.
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.
Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Pan
P
Xu
Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, NL-9700 RB Groningen, The Netherlands;
Maaike H
MH
Oosterveer
Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Sokrates
S
Stein
Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Hadrien
H
Demagny
Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Dongryeol
D
Ryu
Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Norman
N
Moullan
Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Xu
X
Wang
Institute of the Physics of Biological Systems, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Emine
E
Can
Department of Biology, Institute for Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zurich, Switzerland.
Nicola
N
Zamboni
Institute of the Physics of Biological Systems, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Arnaud
A
Comment
Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Johan
J
Auwerx
Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
Kristina
K
Schoonjans
D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D004052:Diethylnitrosamine; D015972:Gene Expression Regulation, Neoplastic; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D046912:Multiprotein Complexes; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D005973:Glutamine; D004052:Diethylnitrosamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005972:Glutaminase
Hepatocellular carcinoma; NADPH; anaplerosis; cancer metabolism; mTOR; mitochondria; nuclear receptor NR5A2