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Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

Capece, Daria, D'Andrea, Daniel, Begalli, Federica, Goracci, Laura, Tornatore, Laura, Alexander, James L., Di Veroli, Alessandra, Leow, Shi-Chi, Vaiyapuri, Thamil S., Ellis, James K., Verzella, Daniela, Bennett, Jason, Savino, Luca, Ma, Yue, McKenzie, James S., Doria, Maria Luisa, Mason, Sam E., Chng, Kern Rei, Keun, Hector C., Frost, Gary, Tergaonkar, Vinay, Broniowska, Katarzyna, Stunkel, Walter, Takats, Zoltan, Kinross, James M., Cruciani, Gabriele and Franzoso, Guido 2021. Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma. Journal of Clinical Investigation 131 (11) , e137845. 10.1172/JCI137845

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Abstract

The ability to adapt to low-nutrient microenvironments is essential for tumor cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription factor pathway associates with advanced disease stages and shorter survival in patients with CRC. NF-κB has been shown to drive tumor-promoting inflammation, cancer cell survival, and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in patients with CRC is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB–regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC cell survival via cell-autonomous mechanisms that fuel fatty acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight patients with CRC. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype 4 (CMS4), which is associated with obesity, stemness, and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator HNF4A in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavorable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License
Publisher: American Society for Clinical Investigation
ISSN: 1558-8238
Date of First Compliant Deposit: 23 February 2022
Date of Acceptance: 14 April 2021
Last Modified: 02 Mar 2022 10:00
URI: https://orca.cardiff.ac.uk/id/eprint/147762

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