肥胖流行与结肠癌进展加剧有关。由于脂滴 (LD) 促进肿瘤生长，我们旨在确定负责 LD 生物发生的二酰基转移酶（二酰基甘油邻酰基转移酶 1 和 2 [DGAT1/2]）在肥胖介导的结肠肿瘤发生中的重要性。人类结肠癌样本，采用高脂肪饮食的结肠癌细胞、结肠球和 ApcMin/结肠癌小鼠模型。对于 DGAT1/2 抑制，使用酶抑制剂和小干扰 RNA。评估表达、途径、细胞周期和生长。 CUT的生物信息学分析

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.Human colon cancer samples, colon cancer cells, colonospheres, and ApcMin/+ 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.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 ApcMin/+ 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.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.