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bioRxiv · 10.1101/2022.05.20.492006

PGC1β and ERRα promote glutamine metabolism and colorectal cancer survival via transcriptional regulation of PCK2

Fisher, K. W. W.·Frodyma, D.·Troia, T.·Berg, J. A.·Lewis, R. E.·Rao, C.·Svoboda, R.·Thomas, V.·Shinde, D.
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Abstract

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.

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Fisher, K. W. W., Frodyma, D., Troia, T., Berg, J. A., Lewis, R. E., Rao, C., Svoboda, R., Thomas, V., Shinde, D.. 2022-05-20. PGC1β and ERRα promote glutamine metabolism and colorectal cancer survival via transcriptional regulation of PCK2. https://doi.org/10.1101/2022.05.20.492006

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