Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma
Daria Capece, … , Gabriele Cruciani, Guido Franzoso
Daria Capece, … , Gabriele Cruciani, Guido Franzoso
Published April 20, 2021
Citation Information: J Clin Invest. 2021;131(11):e137845. https://doi.org/10.1172/JCI137845.
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Research Article Metabolism Oncology

Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma

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.

Authors

Daria Capece, Daniel D’Andrea, Federica Begalli, Laura Goracci, Laura Tornatore, James L. Alexander, Alessandra Di Veroli, Shi-Chi Leow, Thamil S. Vaiyapuri, James K. Ellis, Daniela Verzella, Jason Bennett, Luca Savino, Yue Ma, James S. McKenzie, Maria Luisa Doria, Sam E. Mason, Kern Rei Chng, Hector C. Keun, Gary Frost, Vinay Tergaonkar, Katarzyna Broniowska, Walter Stunkel, Zoltan Takats, James M. Kinross, Gabriele Cruciani, Guido Franzoso

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Figure 1

NF-κB is activated in the mesenchymal CMS4 CRC subtype and regulates lipid metabolism upon starvation.

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NF-κB is activated in the mesenchymal CMS4 CRC subtype and regulates lip...
Box plots showing the median z scores of the NF-κB-activation (A) and inflammatory (B) gene signatures in each CMS subtype from patients with CRC (n = 296) in The Cancer Genome Atlas (TCGA) data set. Shown in the box plots are the median values (horizontal lines), 25th to 75th percentiles (box outlines), and highest and lowest values within 1.5 times the interquartile range (vertical lines). Notches denote the 95% confidence interval of the medians. Samples from each CMS subtype were compared with other CRC samples by using 2-tailed Student’s t test. ***P < 0.001. Statistical significance for multiple comparisons was calculated using the Kruskal-Wallis test (P < 2.2 × 10–16). (C) Hierarchical clustering of the 1795 metabolic genes present in the Reactome database from the patients in A and B, arranged according to CMS subtype. The z scores of gene expression are depicted as a gradient from azure (low expression) to orange (high expression). Yellow, CMS1; blue, CMS2; red, CMS3; green, CMS4. (D) Metabolite set enrichment analysis of significantly deregulated biochemicals (q < 0.05) in MEFs expressing RelA-specific (RelA) relative to nonspecific (ns) shRNAs (n = 5), cultured under normal conditions (0) or for the indicated times under GL. P values were corrected using the Benjamini-Hochberg false-discovery rate (FDR) procedure. Orange, overenrichment (up); azure, underenrichment (down). (E) Heatmap showing the log2 fold change of metabolic species in the indicated lipid classes in RelA-deficient relative to control MEFs treated as in D. Shown are the lipid species having a value different from 0 in at least 1 of the time points investigated. Orange, increased abundance; azure, decreased abundance. Framed in black are the lipid classes showing statistically significant accumulation, as determined by a hypergeometric test, corrected using the Benjamini-Hochberg procedure (CE: d2, q = 4.55 × 10–2; triacylglycerol: d1, q = 4.44 × 10–7; d2, q=1.19 × 10–5). For D and E, metabolic analysis were conducted at Metabolon.