biostudies-literatureFrodyma DEThe University of Nebraska Advanced Microscopy core facilityAmerican Cancer SocietyFred &amp; Pamela Buffett Cancer CenterNational Institutes of Health/National Institute of Allergy and Infectious DiseasesDr. Danielle Frodyma. NCINIAID NIH HHSDr. Robert E. Lewis. NCINational Cancer InstituteNCI NIH HHSDr. Jordan A. Berg The University of Nebraska Genomics core facilityNIGMS NIH HHSDr. Kurt W. Fisher. NCI4879https://www.ebi.ac.uk/biostudies/studies/S-EPMC9562873biostudies-literatureUnknown14(19)<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Discussion</h4>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.CancersPGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.PMC9562873IRG-18-240-04-IRG.P30 CA036727P30 GM1107681P30GM110768-01GM121316P30 GM106397P20GM103427-14P20 GM121316R01-AI125588P01-AI83211GM106397T32 CA009476—P30CA036727CA009476F99CA253744P20 GM103427P01 AI083211P30CA036727CA22287R01 AI125588F99 CA253744NIH P30 GM106397Lewis RETroia TCRao CFrodyma DEBerg JAThomas VCShinde DDSvoboda RAFisher KWfalsePGC-1β and ERRα Promote Glutamine Metabolism and Colorectal Cancer Survival via Transcriptional Upregulation of PCK2.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Discussion</h4>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.2022-01-01T00:00:00Z2022 Oct2025-04-26T22:05:52.401Z2025-02-19T01:02:55.031ZS-EPMC95628733623080210.3390/cancers14194879