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, Savkovic Suzana D
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Gastroenterology. 2025 Feb;168(2):286-299.e6. doi: 10.1053/j.gastro.2024.09.011. Epub 2024 Sep 18.
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.
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.
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.
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.
肥胖流行与结肠癌进展增加有关。由于脂滴为肿瘤生长提供能量，我们旨在确定负责脂滴生物合成的二酰基转移酶（二酰甘油O-酰基转移酶1和2 [DGAT1/2]）在肥胖介导的结肠肿瘤发生中的意义。
使用人类结肠癌样本、结肠癌细胞、结肠球以及高脂饮食喂养的Apc结肠癌小鼠模型。为抑制DGAT1/2，使用了酶抑制剂和小干扰RNA。评估了其表达、信号通路、细胞周期和生长情况。对CUT&RUN和RNA测序数据进行了生物信息学分析。
人类结肠癌组织中DGAT1/2水平随疾病严重程度和肥胖程度（与正常相比）显著升高。其水平在人类结肠癌细胞（与未转化细胞相比）中升高，并因肥胖中普遍存在的脂肪酸而进一步增强；DGAT2表达增加依赖于MYC。抑制DGAT1/2可通过减弱PI3K来提高FOXO3活性，从而导致依赖于MYC的DGAT2表达减少和脂滴积累，提示存在反馈机制。这种抑制通过FOXO3/p27kip1细胞周期阻滞减弱了结肠癌细胞和结肠球的生长，并减少了高脂饮食喂养的Apc小鼠的结肠肿瘤。转录组分析显示，抑制DGAT1/2靶向人类结肠癌和结肠隐窝中的代谢和致瘤途径，将人类结肠癌样本与正常样本区分开来。进一步分析表明，这种抑制可预测结肠癌患者的无进展状态和生存期。
这是肥胖促进的结肠癌中DGAT1/2依赖性代谢和致瘤重塑的新机制，为未来开发结肠癌患者的有效治疗方法提供了平台。
