PGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.

BACKGROUND

Previous studies have shown that Peroxisome Proliferator-Activated Receptor Gamma, Coactivator 1 Beta (PGC-1β) and Estrogen-Related Receptor Alpha (ERRα) are over-expressed in colorectal cancer and promote tumor survival.

METHODS

In this study, we use immunoprecipitation of epitope tagged endogenous PGC-1β and inducible PGC-1β mutants to show that amino acid motif LRELL on PGC-1β is responsible for the physical interaction with ERRα and promotes ERRα mRNA and protein expression. We use RNAsequencing to determine the genes regulated by both PGC-1β & ERRα and find that mitochondrial Phosphoenolpyruvate Carboxykinase 2 (PCK2) is the gene that decreased most significantly after depletion of both genes.

RESULTS

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 ERRα decreased anchorage-independent growth and glutamine metabolism, which could not be rescued by plasmid derived expression of PCK2.

DISCUSSION

These findings suggest that transcriptional control of PCK2 is one mechanism used by PGC-1β and ERRα to promote glutamine metabolism and colorectal cancer cell survival.