VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway
Abstract Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. H...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03901-7 |
| _version_ | 1819025122529378304 |
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| author | Ying Tong Jinyan Kai Shuo Wang Yiwen Yu Suhong Xie Hui Zheng Yanchun Wang Yixuan Liu Keyu Zhu Xiaolin Guan Lin Guo Renquan Lu |
| author_facet | Ying Tong Jinyan Kai Shuo Wang Yiwen Yu Suhong Xie Hui Zheng Yanchun Wang Yixuan Liu Keyu Zhu Xiaolin Guan Lin Guo Renquan Lu |
| author_sort | Ying Tong |
| collection | DOAJ |
| description | Abstract Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel–Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs. |
| first_indexed | 2024-12-21T05:05:40Z |
| format | Article |
| id | doaj.art-8a5c2676bc93491f92ad54a3aa26a62b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-21T05:05:40Z |
| publishDate | 2021-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-8a5c2676bc93491f92ad54a3aa26a62b2022-12-21T19:15:08ZengNature Publishing GroupCell Death and Disease2041-48892021-06-0112711310.1038/s41419-021-03901-7VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathwayYing Tong0Jinyan Kai1Shuo Wang2Yiwen Yu3Suhong Xie4Hui Zheng5Yanchun Wang6Yixuan Liu7Keyu Zhu8Xiaolin Guan9Lin Guo10Renquan Lu11Department of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People’s HospitalDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterDepartment of Clinical Laboratory, Fudan University Shanghai Cancer CenterAbstract Clear cell renal cell carcinomas (ccRCC) reprogram carbon metabolism responses to hypoxia, thereby promoting utilization of glutamine. Recently, sirtuin 4 (SIRT4), a novel molecular has turned out to be related to alternating glutamine metabolism and modulating the tumor microenvironment. However, the role of SIRT4 in ccRCC remains poorly understood. Here, we illustrated that the expression of SIRT4 is markedly reduced in cancerous tissues, and closely associated with malignancy stage, grade, and prognosis. In ccRCC cells, SIRT4 exerted its proapoptotic activity through enhancing intracellular reactive oxygen species (ROS). Heme oxygenase-1 (HO-1) is part of an endogenous defense system against oxidative stress. Nevertheless, overexpression of SIRT4 hindered the upregulation of HO-1 in von Hippel–Lindau (VHL)-proficient cells and repressed its expression in VHL-deficient cells. This discrepancy indicated that competent VHL withstands the inhibitory role of SIRT4 on HIF-1α/HO-1. Functionally, overexpression of HO-1 counteracted the promotional effects of SIRT4 on ROS accumulation and apoptosis. Mechanistically, SIRT4 modulates ROS and HO-1 expression via accommodating p38-MAPK phosphorylation. By contrast, downregulation of p38-MAPK by SB203580 decreased intracellular ROS level and enhanced the expression of HO-1. Collectively, this work revealed a potential role for SIRT4 in the stimulation of ROS and the modulation of apoptosis. SIRT4/HO-1 may act as a potential therapeutic target, especially in VHL-deficient ccRCCs.https://doi.org/10.1038/s41419-021-03901-7 |
| spellingShingle | Ying Tong Jinyan Kai Shuo Wang Yiwen Yu Suhong Xie Hui Zheng Yanchun Wang Yixuan Liu Keyu Zhu Xiaolin Guan Lin Guo Renquan Lu VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway Cell Death and Disease |
| title | VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway |
| title_full | VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway |
| title_fullStr | VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway |
| title_full_unstemmed | VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway |
| title_short | VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway |
| title_sort | vhl regulates the sensitivity of clear cell renal cell carcinoma to sirt4 mediated metabolic stress via hif 1α ho 1 pathway |
| url | https://doi.org/10.1038/s41419-021-03901-7 |
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