PGC-1β and ERRα promote glutamine metabolism and colorectal cancer survival via transcriptional regulation of PCK2

Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1{beta}) and Estrogen-Related Receptor Alpha (ERR) are over-expressed in colorectal cancer and promote tumor survival. In this study, we show that amino acid motif LRELL on PGC-1{beta} is responsible for the physical interaction with ERR and promotes ERR mRNA and protein expression. We used RNAsequencing to determine the genes regulated by both PGC-1{beta} & ERR and found that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) was the gene that decreased most significantly after depletion of both genes. Depletion of PCK2 in colorectal cancer cells was sufficient to reduce anchorage-independent growth and inhibit glutamine utilization by the TCA cycle. Lastly, shRNA-mediated depletion of ERR decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2. These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1{beta} and ERR to promote glutamine metabolism and colorectal cancer cell survival.