TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway
Abstract Papillary renal cell carcinoma (pRCC) is a challenging renal cell carcinoma subtype with poor prognosis and limited treatment options due to the lack of reliable biomarkers. The tripartite motif (TRIM) protein family is involved in various cellular processes, including oncogenesis. Among th...
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Nature Publishing Group
2025-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07913-5 |
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| author | Haiyan Weng Jiaxin Zhong Ruiyi Yang Beinan Han Qiuchen Kong Yimin Zhang Wei Zhuang Jingyi Wang Hai Hu Xiaorong Lin |
| author_facet | Haiyan Weng Jiaxin Zhong Ruiyi Yang Beinan Han Qiuchen Kong Yimin Zhang Wei Zhuang Jingyi Wang Hai Hu Xiaorong Lin |
| author_sort | Haiyan Weng |
| collection | DOAJ |
| description | Abstract Papillary renal cell carcinoma (pRCC) is a challenging renal cell carcinoma subtype with poor prognosis and limited treatment options due to the lack of reliable biomarkers. The tripartite motif (TRIM) protein family is involved in various cellular processes, including oncogenesis. Among these, TRIM59 has emerged as a potential oncogene in multiple cancers; however, its role in pRCC progression remains unclear. Here, by using RNA sequencing data from The Cancer Genome Atlas (TCGA) and LASSO Cox regression analysis, we developed a prognostic model based on TRIM family genes for pRCC, with RiskScore demonstrating potential as a prognostic biomarker. Through the comparison of overall survival (OS) and progression-free survival (PFS), we identified TRIM59 as the primary research target. TRIM59 was markedly overexpressed in pRCC tissues, and correlated with poor OS. Functional studies showed that TRIM59 knockdown inhibited pRCC cell proliferation and induced mitochondrial-related apoptosis both in vitro and in vivo. Mechanistically, TRIM59 facilitated K27- and K63-linked ubiquitination and degradation of Acetyl-CoA Acetyltransferase 1 (ACAT1) at lysine 174 (K174), a critical enzyme in mitochondrial lipid metabolism. This disruption of lipid homeostasis in clear cell renal carcinoma (pRCC), particularly in mitochondrial cardiolipin metabolism, inhibited mitochondria-dependent apoptosis and, consequently, enhanced tumorigenesis. These findings suggest TRIM59 as a biomarker and potential therapeutic target, supporting precision oncology strategies for pRCC treatment. |
| format | Article |
| id | doaj-art-da34ee8cbc5d4ee59015d705c7b35172 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-da34ee8cbc5d4ee59015d705c7b351722025-08-20T03:06:10ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111510.1038/s41419-025-07913-5TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathwayHaiyan Weng0Jiaxin Zhong1Ruiyi Yang2Beinan Han3Qiuchen Kong4Yimin Zhang5Wei Zhuang6Jingyi Wang7Hai Hu8Xiaorong Lin9Department of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDepartment of Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityDiagnosis and Treatment Center of Breast Diseases, Shantou Central HospitalDepartment of Pharmacy, Women and Children’s Hospital, School of Medicine, Xiamen UniversityDepartment of Otolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen UniversityBreast Cancer Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of SciencesDiagnosis and Treatment Center of Breast Diseases, Shantou Central HospitalAbstract Papillary renal cell carcinoma (pRCC) is a challenging renal cell carcinoma subtype with poor prognosis and limited treatment options due to the lack of reliable biomarkers. The tripartite motif (TRIM) protein family is involved in various cellular processes, including oncogenesis. Among these, TRIM59 has emerged as a potential oncogene in multiple cancers; however, its role in pRCC progression remains unclear. Here, by using RNA sequencing data from The Cancer Genome Atlas (TCGA) and LASSO Cox regression analysis, we developed a prognostic model based on TRIM family genes for pRCC, with RiskScore demonstrating potential as a prognostic biomarker. Through the comparison of overall survival (OS) and progression-free survival (PFS), we identified TRIM59 as the primary research target. TRIM59 was markedly overexpressed in pRCC tissues, and correlated with poor OS. Functional studies showed that TRIM59 knockdown inhibited pRCC cell proliferation and induced mitochondrial-related apoptosis both in vitro and in vivo. Mechanistically, TRIM59 facilitated K27- and K63-linked ubiquitination and degradation of Acetyl-CoA Acetyltransferase 1 (ACAT1) at lysine 174 (K174), a critical enzyme in mitochondrial lipid metabolism. This disruption of lipid homeostasis in clear cell renal carcinoma (pRCC), particularly in mitochondrial cardiolipin metabolism, inhibited mitochondria-dependent apoptosis and, consequently, enhanced tumorigenesis. These findings suggest TRIM59 as a biomarker and potential therapeutic target, supporting precision oncology strategies for pRCC treatment.https://doi.org/10.1038/s41419-025-07913-5 |
| spellingShingle | Haiyan Weng Jiaxin Zhong Ruiyi Yang Beinan Han Qiuchen Kong Yimin Zhang Wei Zhuang Jingyi Wang Hai Hu Xiaorong Lin TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway Cell Death and Disease |
| title | TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway |
| title_full | TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway |
| title_fullStr | TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway |
| title_full_unstemmed | TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway |
| title_short | TRIM59 suppresses mitochondrial-associated apoptosis to facilitate progression in papillary renal cell carcinoma via the ACAT1-cardiolipin pathway |
| title_sort | trim59 suppresses mitochondrial associated apoptosis to facilitate progression in papillary renal cell carcinoma via the acat1 cardiolipin pathway |
| url | https://doi.org/10.1038/s41419-025-07913-5 |
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