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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 14, 2024 |
| Title |
Obesity facilitated colon cancer progression is mediated by increased diacylglycerol o-acyltransferases 1 and 2 (DGAT1/2) levels [RNA-seq] |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Background & Aims: The obesity epidemic is associated with increased colon cancer progression. As lipid droplets (LDs) fuel tumor growth, we aim to determine the significance of diacyltransferases, DGAT1/2, responsible for LDs biogenesis, in obesity-mediated colonic tumorigenesis. Methods: 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 siRNA were used. Expression, pathways, cell cycle, and growth were assessed. Bioinformatic analysis of CUT&RUN and RNAseq data was 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 non-transformed) 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 LDs accumulation, 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 colon cancer patients. Conclusion: This is a novel mechanism of DGAT1/2-dependent metabolic and tumorigenic remodeling in obesity-facilitated colon cancer, which provides a platform for the future development of effective treatments for colon cancer patients.
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| Overall design |
RNA-Seq of HT29 adherent and colonospheres treated with DGAT1/2 inhibitors. RNA-Seq of Apcmin/+ mice colon treated with DGAT1/2 Inhibitors and fed regular or high fat diet
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| Web link |
https://www.sciencedirect.com/science/article/pii/S0016508524054647?via%3Dihub
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| Contributor(s) |
Ghimire J, Collins ME, Snarski P, King AN, Ruiz E, Iftikhar R, Penrose HM, Moroz K, Rorison T, Baddoo M, Naeem M, Zea AH, Magness ST, Flemington EF, Crawford SE, Savkovic SD |
| Citation(s) |
39299402 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA252055 |
Regulation of DGAT - dependent lipogenesis in colonic epithelial growth |
TULANE UNIVERSITY |
Suzana D. Savkovic |
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| Submission date |
Oct 04, 2024 |
| Last update date |
Oct 15, 2024 |
| Contact name |
Suzana D Savkovic |
| E-mail(s) |
[email protected]
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| Organization name |
Tulane University
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| Street address |
1430 Tulane Ave JBJ 315
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| City |
NEW ORLEANS |
| State/province |
LA |
| ZIP/Postal code |
70112 |
| Country |
USA |
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| Platforms (2) |
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| Samples (26)
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| Relations |
| BioProject |
PRJNA1168928 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE278785_HFD_DGAT1_2Treated_vs_HFD_Untreated.xlsx |
5.8 Mb |
(ftp)(http) |
XLSX |
| GSE278785_HT29_cells_DGAT1_2_Inhibitors_Vs_Control._Summary._Genes.xlsx |
8.5 Mb |
(ftp)(http) |
XLSX |
| GSE278785_HT29_colonospheres_DGAT1_2_inhibitors_vs_Control._Summary._Genes.xlsx |
3.9 Mb |
(ftp)(http) |
XLSX |
| GSE278785_RD_DGAT1_2Treated_vs_RD_Untreated.xlsx |
5.5 Mb |
(ftp)(http) |
XLSX |
| GSE278785_RD_Untreated_vs_HFD_Untreated.xlsx |
5.6 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
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