E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα
Pancreatic cancer is one of the most fatal cancers in humans. While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly up...
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| Veröffentlicht in: | Oncogene 2021-01, Vol.40 (2), p.262-276 |
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| creator | Chen, Leifeng Yuan, Rongfa Wen, Chongyu Liu, Tiande Feng, Qian Deng, Xueqiang Du, Yunyan Peng, Xiaogang |
| description | Pancreatic cancer is one of the most fatal cancers in humans. While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBPα, directly binding to C/EBPα, and promoting its ubiquitination and degradation. Together, these results identify a mechanism used by pancreatic cancer cells to survive the nutrient-poor tumour microenvironment and also provide insight regarding the role of UBR5 in pancreatic cancer cell adaptation to metabolic stresses. |
| doi_str_mv | 10.1038/s41388-020-01527-1 |
| format | Article |
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While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBPα, directly binding to C/EBPα, and promoting its ubiquitination and degradation. Together, these results identify a mechanism used by pancreatic cancer cells to survive the nutrient-poor tumour microenvironment and also provide insight regarding the role of UBR5 in pancreatic cancer cell adaptation to metabolic stresses.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-01527-1</identifier><identifier>PMID: 33122826</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/2 ; 13/89 ; 13/95 ; 14 ; 14/1 ; 14/33 ; 14/35 ; 59 ; 631/67/395 ; 692/53/2423 ; Animals ; Apoptosis ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; CCAAT-Enhancer-Binding Protein-alpha - chemistry ; CCAAT-Enhancer-Binding Protein-alpha - genetics ; CCAAT-Enhancer-Binding Protein-alpha - metabolism ; Cell Biology ; Cell Proliferation ; Fructose-Bisphosphatase - genetics ; Fructose-Bisphosphatase - metabolism ; Gene Expression Regulation, Neoplastic ; Glycolysis ; Human Genetics ; Humans ; Internal Medicine ; Male ; Malnutrition ; Medicine ; Medicine & Public Health ; Metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Microenvironments ; Oncology ; Pancreatic cancer ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Phenotypes ; Protein Stability ; Tumor Cells, Cultured ; Tumor microenvironment ; Tumors ; Ubiquitin ; Ubiquitin-protein ligase ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination ; Xenograft Model Antitumor Assays</subject><ispartof>Oncogene, 2021-01, Vol.40 (2), p.262-276</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-a6461f96c7f3e1cca5f140de4efbee345e13bb782fe6efad65679a3e6a506afd3</citedby><cites>FETCH-LOGICAL-c375t-a6461f96c7f3e1cca5f140de4efbee345e13bb782fe6efad65679a3e6a506afd3</cites><orcidid>0000-0001-5957-1906 ; 0000-0002-8173-5118</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-020-01527-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-020-01527-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33122826$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Leifeng</creatorcontrib><creatorcontrib>Yuan, Rongfa</creatorcontrib><creatorcontrib>Wen, Chongyu</creatorcontrib><creatorcontrib>Liu, Tiande</creatorcontrib><creatorcontrib>Feng, Qian</creatorcontrib><creatorcontrib>Deng, Xueqiang</creatorcontrib><creatorcontrib>Du, Yunyan</creatorcontrib><creatorcontrib>Peng, Xiaogang</creatorcontrib><title>E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Pancreatic cancer is one of the most fatal cancers in humans. While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBPα, directly binding to C/EBPα, and promoting its ubiquitination and degradation. 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While it thrives in a state of malnutrition, the mechanism by which pancreatic cancer cells adapt to metabolic stress through metabolic reprogramming remains unclear. Here, we showed that UBR5, an E3 ubiquitin ligase, was significantly upregulated in pancreatic cancer patient samples compared to the levels in adjacent normal tissues. Levels of UBR5 were closely related to a malignant phenotype and shorter survival among pancreatic cancer patients. Multivariate analyses also revealed that UBR5 overexpression was an independent predictor of poor outcomes among patients with pancreatic cancer. Functional assays revealed that UBR5 contributes to the growth of pancreatic cancer cells by inducing aerobic glycolysis. Furthermore, we demonstrated that UBR5 knockdown increased levels of fructose-1,6-bisphosphatase (FBP1), an important negative regulator in the process of aerobic glycolysis in many cancers. We found a significant negative correlation between levels of UBR5 and FBP1, further demonstrating that UBR5-induced aerobic glycolysis is dependent on FBP1 in pancreatic cancer cells. Mechanistically, UBR5 regulates FBP1 expression by modulating C/EBPα, directly binding to C/EBPα, and promoting its ubiquitination and degradation. Together, these results identify a mechanism used by pancreatic cancer cells to survive the nutrient-poor tumour microenvironment and also provide insight regarding the role of UBR5 in pancreatic cancer cell adaptation to metabolic stresses.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33122826</pmid><doi>10.1038/s41388-020-01527-1</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0001-5957-1906</orcidid><orcidid>https://orcid.org/0000-0002-8173-5118</orcidid></addata></record> |
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| subjects | 13 13/1 13/2 13/89 13/95 14 14/1 14/33 14/35 59 631/67/395 692/53/2423 Animals Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism CCAAT-Enhancer-Binding Protein-alpha - chemistry CCAAT-Enhancer-Binding Protein-alpha - genetics CCAAT-Enhancer-Binding Protein-alpha - metabolism Cell Biology Cell Proliferation Fructose-Bisphosphatase - genetics Fructose-Bisphosphatase - metabolism Gene Expression Regulation, Neoplastic Glycolysis Human Genetics Humans Internal Medicine Male Malnutrition Medicine Medicine & Public Health Metabolism Mice Mice, Inbred BALB C Mice, Nude Microenvironments Oncology Pancreatic cancer Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Phenotypes Protein Stability Tumor Cells, Cultured Tumor microenvironment Tumors Ubiquitin Ubiquitin-protein ligase Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination Xenograft Model Antitumor Assays |
| title | E3 ubiquitin ligase UBR5 promotes pancreatic cancer growth and aerobic glycolysis by downregulating FBP1 via destabilization of C/EBPα |
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