Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels
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 tumor...
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| Veröffentlicht in: | Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2024-09 |
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| creator | 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. |
| description | 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 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.
[Display omitted]
Increased levels of diacylglycerol o-acyltransferases 1 and 2, which drive lipid droplet accumulation in human colon cancer, via a novel mechanism, may offer new therapeutic targets for treating colon cancer in obese patients. |
| doi_str_mv | 10.1053/j.gastro.2024.09.011 |
| format | Article |
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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.
[Display omitted]
Increased levels of diacylglycerol o-acyltransferases 1 and 2, which drive lipid droplet accumulation in human colon cancer, via a novel mechanism, may offer new therapeutic targets for treating colon cancer in obese patients.</description><identifier>ISSN: 0016-5085</identifier><identifier>ISSN: 1528-0012</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2024.09.011</identifier><identifier>PMID: 39299402</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Colon Cancer ; DGAT1 ; DGAT2 ; FOXO3 ; Lipid Droplets ; Obesity</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2024-09</ispartof><rights>2024 The Authors</rights><rights>Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2021-9dd335bc0efd325888e654c3584e9475f6d773f9fdfe08fde985974c1010535e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1053/j.gastro.2024.09.011$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39299402$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghimire, Jenisha</creatorcontrib><creatorcontrib>Collins, Morgan E.</creatorcontrib><creatorcontrib>Snarski, Patricia</creatorcontrib><creatorcontrib>King, Angelle N.</creatorcontrib><creatorcontrib>Ruiz, Emmanuelle</creatorcontrib><creatorcontrib>Iftikhar, Rida</creatorcontrib><creatorcontrib>Penrose, Harrison M.</creatorcontrib><creatorcontrib>Moroz, Krzysztof</creatorcontrib><creatorcontrib>Rorison, Tyler</creatorcontrib><creatorcontrib>Baddoo, Melody</creatorcontrib><creatorcontrib>Naeem, Muhammad Anas</creatorcontrib><creatorcontrib>Zea, Arnold H.</creatorcontrib><creatorcontrib>Magness, Scott T.</creatorcontrib><creatorcontrib>Flemington, Erik F.</creatorcontrib><creatorcontrib>Crawford, Susan E.</creatorcontrib><creatorcontrib>Savkovic, Suzana D.</creatorcontrib><title>Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels</title><title>Gastroenterology (New York, N.Y. 1943)</title><addtitle>Gastroenterology</addtitle><description>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 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.
[Display omitted]
Increased levels of diacylglycerol o-acyltransferases 1 and 2, which drive lipid droplet accumulation in human colon cancer, via a novel mechanism, may offer new therapeutic targets for treating colon cancer in obese patients.</description><subject>Colon Cancer</subject><subject>DGAT1</subject><subject>DGAT2</subject><subject>FOXO3</subject><subject>Lipid Droplets</subject><subject>Obesity</subject><issn>0016-5085</issn><issn>1528-0012</issn><issn>1528-0012</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kMFuEzEQhi0EoqHwBgj5yGWX8XqdtS9IVaAQKSgc4Gw59jhy5KyLvanYt-mz9MlwlMKR02hG3z-j-Qh5y6BlIPiHQ7s3Zcqp7aDrW1AtMPaMLJjoZAPAuudkUcuyESDFFXlVygEAFJfsJbniqlOqh25Bfm93WMI0N7fGhhgmM6GjqxTTSFdmtJjp95z2GUsJdbQu9Bu6cIYeH3bz48N6tBlNqZlPwdg57uNcMynSbXNT2ymbsXjMlSiUUTM62tEN3mMsr8kLb2LBN0_1mvy8_fxj9bXZbL-sVzebxta_WKOc41zsLKB3vBNSSlyK3nIhe1T9IPzSDQP3yjuPIL1DJYUaesvgLEkgvybvL3vvcvp1wjLpYygWYzQjplPRnMHAxCA6qGh_QW1OpWT0-i6Ho8mzZqDP6_RBX5zrs3MNSlfnNfbu6cJpd0T3L_RXcgU-XoD6Nt4HzLrYgFWuCxntpF0K_7_wB9peloU</recordid><startdate>20240918</startdate><enddate>20240918</enddate><creator>Ghimire, Jenisha</creator><creator>Collins, Morgan E.</creator><creator>Snarski, Patricia</creator><creator>King, Angelle N.</creator><creator>Ruiz, Emmanuelle</creator><creator>Iftikhar, Rida</creator><creator>Penrose, Harrison M.</creator><creator>Moroz, Krzysztof</creator><creator>Rorison, Tyler</creator><creator>Baddoo, Melody</creator><creator>Naeem, Muhammad Anas</creator><creator>Zea, Arnold H.</creator><creator>Magness, Scott T.</creator><creator>Flemington, Erik F.</creator><creator>Crawford, Susan E.</creator><creator>Savkovic, Suzana D.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20240918</creationdate><title>Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels</title><author>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.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2021-9dd335bc0efd325888e654c3584e9475f6d773f9fdfe08fde985974c1010535e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Colon Cancer</topic><topic>DGAT1</topic><topic>DGAT2</topic><topic>FOXO3</topic><topic>Lipid Droplets</topic><topic>Obesity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghimire, Jenisha</creatorcontrib><creatorcontrib>Collins, Morgan E.</creatorcontrib><creatorcontrib>Snarski, Patricia</creatorcontrib><creatorcontrib>King, Angelle N.</creatorcontrib><creatorcontrib>Ruiz, Emmanuelle</creatorcontrib><creatorcontrib>Iftikhar, Rida</creatorcontrib><creatorcontrib>Penrose, Harrison M.</creatorcontrib><creatorcontrib>Moroz, Krzysztof</creatorcontrib><creatorcontrib>Rorison, Tyler</creatorcontrib><creatorcontrib>Baddoo, Melody</creatorcontrib><creatorcontrib>Naeem, Muhammad Anas</creatorcontrib><creatorcontrib>Zea, Arnold H.</creatorcontrib><creatorcontrib>Magness, Scott T.</creatorcontrib><creatorcontrib>Flemington, Erik F.</creatorcontrib><creatorcontrib>Crawford, Susan E.</creatorcontrib><creatorcontrib>Savkovic, Suzana D.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ghimire, Jenisha</au><au>Collins, Morgan E.</au><au>Snarski, Patricia</au><au>King, Angelle N.</au><au>Ruiz, Emmanuelle</au><au>Iftikhar, Rida</au><au>Penrose, Harrison M.</au><au>Moroz, Krzysztof</au><au>Rorison, Tyler</au><au>Baddoo, Melody</au><au>Naeem, Muhammad Anas</au><au>Zea, Arnold H.</au><au>Magness, Scott T.</au><au>Flemington, Erik F.</au><au>Crawford, Susan E.</au><au>Savkovic, Suzana D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels</atitle><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle><addtitle>Gastroenterology</addtitle><date>2024-09-18</date><risdate>2024</risdate><issn>0016-5085</issn><issn>1528-0012</issn><eissn>1528-0012</eissn><abstract>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 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.
[Display omitted]
Increased levels of diacylglycerol o-acyltransferases 1 and 2, which drive lipid droplet accumulation in human colon cancer, via a novel mechanism, may offer new therapeutic targets for treating colon cancer in obese patients.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39299402</pmid><doi>10.1053/j.gastro.2024.09.011</doi><oa>free_for_read</oa></addata></record> |
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| issn | 0016-5085 1528-0012 1528-0012 |
| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | Colon Cancer DGAT1 DGAT2 FOXO3 Lipid Droplets Obesity |
| title | Obesity-Facilitated Colon Cancer Progression Is Mediated by Increased Diacylglycerol O-Acyltransferases 1 and 2 Levels |
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