Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels

Authors

Jenisha Ghimire, Tulane University School of Medicine, New Orleans, LA
Morgan E. Collins, Tulane University School of Medicine, New Orleans, LA
Patricia Snarski, Tulane University School of Medicine, New Orleans, LA
Angelle N. King, Tulane University School of Medicine, New Orleans, LA
Emmanuelle Ruiz, Tulane University School of Medicine, New Orleans, LA
Rida Iftikhar, Tulane University School of Medicine, New Orleans, LA
Harrison M. Penrose, Tulane University School of Medicine, New Orleans, LA
Krzysztof Moroz, Tulane University School of Medicine, New Orleans, LA
Tyler Rorison, Tulane University School of Medicine, New Orleans, LA
Melody Baddoo, Tulane University School of Medicine, New Orleans, LA
Muhammad Anas Naeem, Tulane University School of Medicine, New Orleans, LA
Arnold H. Zea, LSU Health Sciences Center - New OrleansFollow
Scott T. Magness, University of North Carolina-Chapel Hill, Chapel Hill, NC
Erik F. Flemington, Tulane University School of Medicine, New Orleans, LA
Susan E. Crawford, NorthShore University Research Institute, Evanston, IL
Suzana D. Savkovic, Tulane University School of Medicine, New Orleans, LA

Document Type

Article

Publication Date

9-18-2024

Publication Title

Gastroenterology

Abstract

BACKGROUND & AIMS: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aimed to determine the significance of diacyltransferases (diacylglycerol o-acyltransferases 1 and 2 [DGAT1/2]), responsible for LD biogenesis, in obesity-mediated colonic tumorigenesis. METHODS: Human colon cancer samples, colon cancer cells, colonospheres, and Apc colon cancer mouse model on a high-fat diet were employed. For DGAT1/2 inhibition, enzymatic inhibitors and small interfering RNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analyses of CUT&RUN and RNA sequencing data were performed. RESULTS: DGAT1/2 levels in human colon cancer tissue are significantly elevated with disease severity and obesity (vs normal). Their levels are increased in human colon cancer cells (vs nontransformed) and further enhanced by fatty acids prevalent in obesity; augmented DGAT2 expression is MYC-dependent. Inhibition of DGAT1/2 improves FOXO3 activity by attenuating PI3K, resulting in reduced MYC-dependent DGAT2 expression and accumulation of LDs, suggesting feedback. This inhibition attenuated growth in colon cancer cells and colonospheres via FOXO3/p27kip1 cell cycle arrest and reduced colonic tumors in Apc mice on a high-fat diet. Transcriptomic analysis revealed that DGAT1/2 inhibition targeted metabolic and tumorigenic pathways in human colon cancer and colon cancer crypts, stratifying human colon cancer samples from normal. Further analysis revealed that this inhibition is predictive of advanced disease-free state and survival in patients with colon cancer. CONCLUSIONS: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, providing a platform for future development of effective treatments for patients with colon cancer.

PubMed ID

39299402

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Ghimire, Jenisha; Collins, Morgan E.; Snarski, Patricia; King, Angelle N.; Ruiz, Emmanuelle; Iftikhar, Rida; Penrose, Harrison M.; Moroz, Krzysztof; Rorison, Tyler; Baddoo, Melody; Naeem, Muhammad Anas; Zea, Arnold H.; Magness, Scott T.; Flemington, Erik F.; Crawford, Susan E.; and Savkovic, Suzana D., "Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels" (2024). School of Medicine Faculty Publications. 3040.
https://digitalscholar.lsuhsc.edu/som_facpubs/3040
10.1053/j.gastro.2024.09.011