Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults. We generated TRAnsgenic of Cancer of the Kidney (TRACK) mice that express a triple-mutant (P402A, P564A, and N803A) human HIF1α construct specifically in their proximal tubule (PT) cells. We demonstrated that...
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Elsevier
2025-08-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000673 |
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| author | Yuling Chi Shireen Chikara Eduardo Mere Del Aguila Tuo Zhang Jacob B. Geri David M. Nanus Lorraine J. Gudas |
| author_facet | Yuling Chi Shireen Chikara Eduardo Mere Del Aguila Tuo Zhang Jacob B. Geri David M. Nanus Lorraine J. Gudas |
| author_sort | Yuling Chi |
| collection | DOAJ |
| description | Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults. We generated TRAnsgenic of Cancer of the Kidney (TRACK) mice that express a triple-mutant (P402A, P564A, and N803A) human HIF1α construct specifically in their proximal tubule (PT) cells. We demonstrated that the elevated lipid content found in human ccRCCs is mimicked in these TRACK PT cells. Additionally, we reported that ATF4 (activating transcription factor 4), a transcription factor, and its target genes were highly expressed both in human ccRCCs and in TRACK PT cells. To delineate the functions of ATF4 in ccRCC we have now generated TRACK mice in which the ATF4 gene is specifically deleted in PT cells (GCREA∆T). Our genome-wide transcriptomics and proteomics studies show that expression of ∼20 % of mRNAs and proteins is significantly altered in GCREA∆T compared to TRACK kidney cortices. Gene set enrichment analyses (GSEAs) of mRNAs demonstrate that the fatty acid metabolism pathway is upregulated in TRACK vs WT and that, conversely, ATF4 deletion reduces mRNAs in the fatty acid metabolism pathway (e.g., ATP citrate lyase). Moreover, some transcripts elevated in human ccRCC are reduced in GCREA∆T vs. TRACK kidney cortices and cystic, pre-cancerous lesions are also reduced. Thus, ATF4 actions increase both lipid droplet accumulation in this ccRCC model and oncogenesis-related gene expression. These data suggest that ATF4 contributes to the formation of ccRCC tumors and may be a potential therapeutic target. |
| format | Article |
| id | doaj-art-ca5eb8c0184e496f82daa9a45f641355 |
| institution | OA Journals |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-ca5eb8c0184e496f82daa9a45f6413552025-08-20T02:10:06ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-08-016610118810.1016/j.neo.2025.101188Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinomaYuling Chi0Shireen Chikara1Eduardo Mere Del Aguila2Tuo Zhang3Jacob B. Geri4David M. Nanus5Lorraine J. Gudas6Pharmacology Department, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USAPharmacology Department, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USAPharmacology Department, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USAthe Genomics Core, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USAPharmacology Department, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USAthe Department of Medicine, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USAPharmacology Department, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USA; the Department of Medicine, Weill Cornell Medicine of Cornell University, 1300 York Ave, New York, NY 10065, USA; Corresponding author at: Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065-4896, USAClear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults. We generated TRAnsgenic of Cancer of the Kidney (TRACK) mice that express a triple-mutant (P402A, P564A, and N803A) human HIF1α construct specifically in their proximal tubule (PT) cells. We demonstrated that the elevated lipid content found in human ccRCCs is mimicked in these TRACK PT cells. Additionally, we reported that ATF4 (activating transcription factor 4), a transcription factor, and its target genes were highly expressed both in human ccRCCs and in TRACK PT cells. To delineate the functions of ATF4 in ccRCC we have now generated TRACK mice in which the ATF4 gene is specifically deleted in PT cells (GCREA∆T). Our genome-wide transcriptomics and proteomics studies show that expression of ∼20 % of mRNAs and proteins is significantly altered in GCREA∆T compared to TRACK kidney cortices. Gene set enrichment analyses (GSEAs) of mRNAs demonstrate that the fatty acid metabolism pathway is upregulated in TRACK vs WT and that, conversely, ATF4 deletion reduces mRNAs in the fatty acid metabolism pathway (e.g., ATP citrate lyase). Moreover, some transcripts elevated in human ccRCC are reduced in GCREA∆T vs. TRACK kidney cortices and cystic, pre-cancerous lesions are also reduced. Thus, ATF4 actions increase both lipid droplet accumulation in this ccRCC model and oncogenesis-related gene expression. These data suggest that ATF4 contributes to the formation of ccRCC tumors and may be a potential therapeutic target.http://www.sciencedirect.com/science/article/pii/S1476558625000673Clear cell renal cell carcinomaActivating transcription factor 4TranscriptomicsProteomicsFatty acidsATP citrate lyase |
| spellingShingle | Yuling Chi Shireen Chikara Eduardo Mere Del Aguila Tuo Zhang Jacob B. Geri David M. Nanus Lorraine J. Gudas Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma Neoplasia: An International Journal for Oncology Research Clear cell renal cell carcinoma Activating transcription factor 4 Transcriptomics Proteomics Fatty acids ATP citrate lyase |
| title | Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma |
| title_full | Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma |
| title_fullStr | Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma |
| title_full_unstemmed | Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma |
| title_short | Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma |
| title_sort | deletion of the transcription factor atf4 in a model of clear cell renal cell carcinoma |
| topic | Clear cell renal cell carcinoma Activating transcription factor 4 Transcriptomics Proteomics Fatty acids ATP citrate lyase |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000673 |
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