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

Autor:	Ghimire J; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Collins ME; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Snarski P; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., King AN; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Ruiz E; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Iftikhar R; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Penrose HM; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Moroz K; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Rorison T; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Baddoo M; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Naeem MA; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Zea AH; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana., Magness ST; Department of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina; Department of Cell Biology and Physiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina., Flemington EF; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana., Crawford SE; Department of Surgery, NorthShore University Research Institute, affiliate of University of Chicago Pritzker School of Medicine, Evanston, Illinois., Savkovic SD; Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: ssavkovi@tulane.edu.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Sep 18. Date of Electronic Publication: 2024 Sep 18.
DOI:	10.1053/j.gastro.2024.09.011
Abstrakt:	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 LDs biogenesis, in obesity-mediated colonic tumorigenesis. Methods: Human colon cancer samples, colon cancer cells, colonospheres, and Apc Min/+ 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 Min/+ 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. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu