Enhanced triacylglycerol catabolism by carboxylesterase 1 promotes aggressive colorectal carcinoma
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
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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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 3

Ces1d is a direct transcriptional target of NF-κB and one of the top 7 genes upregulated by NF-κB during starvation.

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Ces1d is a direct transcriptional target of NF-κB and one of the top 7 ...
(A) Volcano plots showing differentially expressed metabolic genes (q < 0.05; d0, n = 801; d2, n = 726; d3, n = 833) in RelA-deficient relative to control MEFs (n = 5) cultured under normal conditions (d0) or for 2 (d2) or 3 (d3) days under GL. Reported are the negative log10-transformed adjusted P values plotted against the average log2 fold changes. Dots represent individual genes. Ces1d is depicted as a red dot; the other 6 most markedly downregulated metabolic genes in RelA-deficient relative to control MEFs, across all time points investigated, are depicted as orange dots. (B) qRT-PCR showing the Ces1d mRNA levels in CT-26 cells expressing RelA-specific or ns shRNAs and cultured under normal conditions (0) or for the indicated times under GL. Values denote mean ± SD (n = 3). (C) Western blots showing the protein levels of Ces1d, RelA, and β-actin in CT-26 cells from B. (D) Desthiobiotin-fluorophosphonate activity-based (FP) probe precipitation assays showing the Ces1d-specific serine esterase activity in CT-26 cells from B, as determined by streptavidin-mediated precipitation of the biotin-bound FP probe followed by Western blots with anti–Ces1d antibody. β-actin in the total cell lysates (input) used for the activity-based protein profile (ABPP) assay is shown as a loading control. (E) Chromatin immunoprecipitation assays showing the binding of NF-κB/RelA complexes to κB DNA element 1 (κB1) in the promoter region of Ces1d or the indicated control DNA regions (controls 1–4) in CT-26 cells from B. Values denote mean ± SEM (n = 3). (B–E) Experiments were conducted at least 3 times. (B and E) Statistical significance was calculated by 2-tailed Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001.