| First Author | Xu P | Year | 2016 |
| Journal | Genes Dev | Volume | 30 |
| Issue | 11 | Pages | 1255-60 |
| PubMed ID | 27298334 | Mgi Jnum | J:233307 |
| Mgi Id | MGI:5781243 | Doi | 10.1101/gad.277483.116 |
| Citation | Xu P, et al. (2016) LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer. Genes Dev 30(11):1255-60 |
| abstractText | 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 alpha-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. |
