Format

Send to

Choose Destination
Genes Dev. 2016 Jun 1;30(11):1255-60. doi: 10.1101/gad.277483.116.

LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer.

Author information

1
Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
2
Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University of Groningen, NL-9700 RB Groningen, The Netherlands;
3
Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
4
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;
5
Institute of the Physics of Biological Systems, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland;
6
Department of Biology, Institute for Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, CH-8093 Zurich, Switzerland.

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; NADPH; anaplerosis; cancer metabolism; mTOR; mitochondria; nuclear receptor NR5A2

PMID:
27298334
PMCID:
PMC4911925
DOI:
10.1101/gad.277483.116
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center